Aryl-quinazoline/aryl-2amino-phenyl methanone derivatives

ABSTRACT

A compound of formula (1): wherein R1, R2, R3 and Y are as defined herein, or a pharmaceutically-acceptable and -cleavable ester, or acid addition salt thereof, useful for promoting the release of parathyroid hormone, e.g. for preventing or treating bone conditions which are associated with increased calcium depletion or resorption or in which stimulation of bone formation and calcium fixation in the bone is desirable.

This invention relates to 4-aryl-2(1H)-quinazolinone derivatives andaryl-(2-amino-phenyl)-methanone derivatives and to pharmaceutical usesthereof.

4-Aryl-2(1H)-quinazolinone derivatives and2-substituted-4-aryl-quinazoline derivatives have been describedtogether with their use as promoters of PTH (Parathyroid hormone)release in our co-pending international patent application WO 02/102782.

We have now synthesised additional new 4-aryl-2(1H)-quinazolinonederivatives and aryl-(2-amino-phenyl)-methanone derivatives which haveactivity as promoters of PTH release.

Accordingly the invention provides a compound of formula I

wherein Y is O or S;

R1 represents from 1 to 3 substituents independently selected from OH,SH, halo, NO₂, optionally substituted (lower allyl, lower alkoxy, loweralkenyl, lower alkenyloxy, lower alkynyl, lower alkynyloxy, loweralkanoyl, cycloalkyl, lower alkylsulphone, lower alkylsulphoxide oramino);

R2 represents from 1 to 3 substituents selected from halo, optionallysubstituted (lower alkyl, lower alkenyl, cycloalkyl or lower alkoxy);

R3 is

-   -   A) lower alkyl optionally substituted by 1 to 3 substituents        selected from cycloalkyl, lower alkylene, lower alkyl, Br, F,        CF₃, CN, COOH, lower alkyl-carboxylate, OH, lower alkoxy or        —O_(x)—(CH₂)_(y)—SO_(z)-lower alkyl, wherein x is 0 or 1, y is        0, 1 or 2 and z is 0, 1 or 2; or    -   B) Benzyl which is        -   a. mono- or di-(preferably mono-) substituted by            —O_(x)—(CH₂)_(y)—SO_(z)-lower alkyl or —O_(x)—(CR,            R′)_(y)—COO—R″, wherein x, y and z are as defined above and            R, R′ or R″ is H or lower alkyl (preferably x=0, y=1, R,R′            and R″═H),        -   b. substituted by 1 or 2 substituents selected from            morpholino-lower alkoxy, aryl-lower alkoxy, optionally            N-lower alkyl substituted arylamino-lower alkoxy,        -   c. substituted at the 2-position by lower alkoxy-,            hydroxy-lower alkoxy- or lower alkoxy-lower alkoxy,        -   d. substituted on the —CH₂— group thereof; or    -   C) optionally substituted (aryl-C₂-C₈-alkyl, aryl-C₂-C₈-alkenyl,        heteroarylmethyl or 4-heteroarylbenzyl); or

when R1 is 2 substituents one of which is OH, preferably at the6-position, and the other of which is optionally substituted (loweralkyl, cycloalkyl-lower-alkyl or lower alkenyl), preferably at the5-position, R3 is H or optionally substituted (lower alkyl, aryl,aryl-lower alkyl, arylcycloalkyl, cycloalkyl-lower alkyl,cycloalkenyl-lower alkyl, hetereoaryl-lower alkyl, hetereoaryl, orcarbonyl lower alkyl); or

when R1 is 2-propynyloxy and R2 is isopropyl, R3 is also benzyl which issubstituted by 1 to 3 substituents selected from lower alkyl, loweralkoxy, halo, halo-lower alkyl, e.g. CF₃; or

when R1 is 2-propynyloxy and R2 is isopropyl, R3 is also benzyl which issubstituted by OH and a second and optionally third substituent selectedfrom lower alkyl, lower alkoxy, halo, —O—CH(H or lower alkyl)-COO(H orlower alkyl); or

when R1 is 2-propynyloxy and R2 is cyclopropyl, R3 is also optionallysubstituted lower allyl or benzyl (preferably R3 is also benzyl which issubstituted by 1 to 3 substituents selected from lower alkyl, loweralkoxy, halo, —O—CH(H or lower alkyl)-COO(H or lower alkyl)); or

when Y is S and R1 is as defined above but not methoxy, R3 is alsooptionally substituted benzyl; or

a compound selected from4-(4-isopropyl-phenyl)-1-(3,4-diamino-benzyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one,1-(2,6-dichloro-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one,1-benzyl-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline-2-thione;1-(3,5di-tert-butyl-4-hydroxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one,or1-[3-(2-hydroxy-ethoxy)-benzyl]-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline-2-thione;or

a pharmaceutically-acceptable and -cleavable ester, or acid additionsalt thereof; and

provided that when Y is O and R3 is lower alkyl or cycloalkyl, R3 is notisopropyl or cyclopentyl; or

provided the compound of formula I is not4-(4-isopropyl-phenyl)-6-methoxy-1-pyridin-3-ylmethyl-1.H.-quinazolin-2-one,4-(4-isopropyl-phenyl)-6-methoxy-1-pyridin-2-ylmethyl-1.H.-quinazolin-2-one,1-(6-chloro-pyridin-3-ylmethyl)-4-(4-isopropyl-phenyl)-6-methoxy-1.H.-quinazolin-2-one,4-(4-isopropyl-phenyl)-6-methoxy-1-(5-nitro-furan-2-ylmethyl)-1.H.-quinazolin-2-oneor1-[2-(1.H.-indol-2-yl)-ethyl]-4-(4-isopropyl-phenyl)-6-methoxy-1.H.-quinazolin-2-one,4-(4-isopropyl-phenyl)-6-methoxy-1-phenethyl-1H-quinazolin-2-one,1-(2-hydroxy-2-phenyl-ethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one,methanesulfonic acid2-[4-(4-isopropyl-phenyl)-2-oxo-6-prop-2-ynyloxy-2H-quinazolin-1-ylmethyl]-phenylester, or acetic acid2-[4-(4-isopropyl-phenyl)-2-oxo-6-prop-2-ynyloxy-2H-quinazolin-1-yl]-1-phenyl-ethylester,5-allyl-6-hydroxy-1-isopropyl-4-(4-isopropyl-phenyl)-1.H.-quinazolin-2-one,1-cyclopropylmethyl-4-(o-tolyl)-6-nitro-2(1H)-quinazolinone,1-ethyl-4-(o-tolyl)-6-chloro-2(1H)-quinazolinone,1-cyclopropylmethyl-4-(o-tolyl)-6-chloro-2(1H)-quinazolinone,1-cyclopropylmethyl-4-(o-fluorophenyl)-6-chloro-2(1H)-quinazolinone,1-cyclopropylmethyl-4-(m-chlorophenyl)-6-chloro-2(1H)-quinazolinone,1-cyclopropylmethyl-4-(o-chlorophenyl)-6-nitro-2(1H)-quinazolinone.

Above and elsewhere in the present description the following terms havethe following meanings: Halo or halogen denote I, Br, Cl or F. The term“lower” referred to above and hereinafter in connection with organicradicals or compounds respectively defines such as branched orunbranched with up to and including 7, preferably up to and including 4and advantageously one or two carbon atoms. A lower alkyl group isbranched or unbranched and contains 1 to 7 carbon atoms, preferably 1-4carbon atoms. Lower alkyl represents; for example, methyl, ethyl,propyl, butyl, isopropyl isobutyl, or tertiary butyl. Halo-substitutedlower alkyl is C₁-C₇lower allyl substituted by up to 6 halo atoms. Alower alkoxy group is branched or unbranched and contains 1 to 7 carbonatoms, preferably 1-4 carbon atoms. Lower alkoxy represents for examplemethoxy, ethoxy, propoxy, butoxy, isopropoxy, isobutoxy or tertiarybutoxy. A lower alkene, alkenyl or alkenyloxy group is branched orunbranched and contains 2 to 7 carbon atoms, preferably 1-4 carbon atomsand contains at least one carbon-carbon double bond. Lower alkene loweralkenyl or lower alkenyloxy represents for example vinyl, prop-1-enyl,allyl, butenyl, isopropenyl or isobutenyl and the oxy equivalentsthereof. A lower alkyne, alkynyl or alkynyloxy group is branched orunbranched and contains 2 to 7 carbon atoms, preferably 1-4 carbon atomsand contains at least one carbon-carbon triple bond. Lower alkyne oralkynyl represents for example ethynyl, prop-1-ynyl, propargyl, butynyl,isopropynyl or isobutynyl and the oxy equivalents thereof (In thepresent description, oxygen containing substituents, e.g. alkoxy,alkenyloxy, alkynyloxy, carbonyl, etc. encompass their sulphurcontaining homologues, e.g. thioalkoxy, thioalkenyloxy, thioalkynyloxy,thiocarbonyl, sulphone, sulphoxide etc.). Aryl represents carbocyclic orheterocyclic aryl. Carbocyclic aryl represents monocyclic, bicyclic ortricyclic aryl, for example phenyl or phenyl mono-, di- ortri-substituted by one, two or three radicals selected from lower alkyl,lower alkoxy, aryl, hydroxy, halogen, cyano, trifluoromethyl, loweralkylenedioxy and oxy-C₂-C₃-alkylene; or 1- or 2-naphthyl; or 1- or2-phenanthrenyl. Lower alkylenedioxy is a divalent substituent attachedto two adjacent carbon atoms of phenyl, e.g. methylenedioxy orethylenedioxy. Oxy-C₂-C₃-alkylene is also a divalent substituentattached to two adjacent carbon atoms of phenyl, e.g. oxyethylene oroxypropylene. An example for oxy-C₂-C₃-alkylene-phenyl is2,3-dihydrobenzofuran-5-yl.

Preferred as carbocyclic aryl is naphthyl, phenyl or phenyl mono-, di-or trisubstituted by lower alkoxy, phenyl, halogen, lower alkyl ortrifluoromethyl, especially phenyl or phenyl mono- or disubstituted bylower alkoxy, halogen or trifluoromethyl, and in particular phenyl.

Heterocyclic aryl represents monocyclic or bicyclic heteroaryl, forexample pyridyl, indolyl, quinoxalinyl, quinolinyl, isoquinolinyl,benzothienyl, benzofuranyl, benzopyranyl, benzothiopyranyl,benzothiadiazolyl, furanyl, pyrrolyl, thiazolyl, oxazolyl, isoxazolyl,triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, or any saidradical substituted, especially mono- or di-substituted as definedabove.

Preferably, heterocyclic aryl is pyridyl, pyrimidyl, indolyl,quinoxalinyl, quinolinyl, benzothiadiazolyl, pyrrolyl, thiazolyl,isoxazolyl, triazolyl, tetrazolyl, pyrazolyl, imidazolyl, thienyl, orany said radical substituted, especially mono- or di-substituted asdefined above.

Cycloalkyl represents a saturated cyclic hydrocarbon optionallysubstituted by lower alkyl which contains 3 to 10 ring carbons and isadvantageously cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl optionally substituted by lower alkyl.

R1 may represent from 1 to 3 substituents; though more preferablyrepresent 1 or 2 substituents. The R1 substituents may be present at anyof positions 5, 6, 7 or 8; for instance, at positions 5, 6 or 7, e.g.when R1 represent 2 substituents these may be present at the 5 and 6 or6 and 7 positions. Preferably one of the R1 substituents is at the 6position. R1 as optionally substituted (lower alkyl, lower alkoxy, loweralkenyl, lower alkenyloxy, lower alkynyl, lower alkynyloxy, loweralkanoyl or amino) may be substituted by 1 or 2 substituentsindependently selected from halo, e.g. Cl, lower alkyl, e.g. ethyl ormethyl, lower alkenyl, lower alkynyl, cycloalkyl, e.g. C₃-C₆ cycloalkyl,or cyano.

In a particular embodiment R1 is 2 substituents one of which is OH,preferably at the 6-position, and the other of which is optionallysubstituted (lower alkyl, cycloalkyl lower alkyl or lower alkenyl), e.g.ethyl, propyl, cyclopropylmethyl or allyl, preferably at the 5-position.

Particularly preferred significances for R1 are: propargyloxy, hydroxy,methoxy, ethoxy, allyloxy, 2-chloroethoxy, isopropoxy, n-propoxy,cyclopropylmethoxy, 3-chloropropoxy, 2-methyl-allyloxy, n-butoxy, allyl,amino, acetonitrileoxy, methylamino, dimethylamino, propargylamino, orallylamino; in particular, e.g. as hereinafter described in theExamples.

R2 represents 1, 2 or 3; for instance, 1 substituent, in the 2-positionor 3-position or more preferably in the 4-position, selected from halo,optionally substituted (lower alkyl or amino) in which lower alkyl ispreferably unsubstituted, e.g. branched lower alkyl, and amino ispreferably mono- or di-substituted by lower alkyl.

Preferred significances for R2 include: methyl, ethyl, isopropyl,t-butyl, cyclopropyl or chloro. Most preferably R2 is isopropyl in the4-position.

R3 as alkyl substituted by —O_(x)—(CH₂)_(y)—SO_(z)-lower allyl, may besubstituted by —SO_(z)-lower alkyl, e.g. —S-lower alkyl.

R3 as benzyl which is mono- or di- (preferably mono-) substituted by—O_(x)—(CH₂)_(y)—SO_(z)-lower alkyl, may be benzyl mono-substituted by—SO_(z)-lower alkyl, e.g. —S(O)—CH₃ or —S(O₂)—CH₃.

R3 as benzyl may be substituted on the —CH₂— group thereof, by 1 or 2substituents independently selected from halogen, OH, lower alkyl, e.g.methyl, or lower alkoxy, e.g. methoxy.

R3 as optionally substituted (aryl-C₂-C₈-alkyl, aryl-C₂-C₈-alkenyl,heteroarylmethyl or 4-heteroarylbenzyl) may be substituted by up to 8,typically up to 5, usually 1, 2 or 3 substituents, independentlyselected from halo, nitro, cyano, amino, OH, SH, lower alkyl, loweralkoxy, lower thioalkoxy, lower alkoxycarbonyl, lower alkylsulphonyl,lower alkoxysulphonyl, lower alkylcarbonyloxy, trifluoromethyl,optionally halo-substituted aryl, optionally oxo-substitutedpyrrolidinyl or —X-A-Z,

-   -   wherein    -   —X— is —CO—O—, —O—, —CH₂—O—, —CO—NR5-, —NR5-, —CH₂—NR5-,        —CO—CH₂—, —S—, —S(O)—, —S(O₂)—, —CH₂—S—, CH₂S(O)—, —CH₂S(O₂)—,        —SO—NR5-, —SO₂—NR5-, —NR5-CO—, NR5S(O)—, NR5S(O₂)— or —O—CO—,        where R5 is H or optionally substituted (lower alkyl, lower        alkenyl, lower alkoxy-lower alkyl, aryl lower alkyl or        optionally mono- or di-lower alkyl-substituted amino lower        allyl),    -   -A- is    -   C₁-C₁₀ alkyl, preferably C₃-C₈ alkyl optionally interrupted by        one or more, e.g. up to 4, preferably 1, 2 or 3, of —O—, —S— or        —NR5-, or    -   HO-(lower alkoxy)_(p)-, e.g. HO(ethoxy)_(p), or lower        alkoxy-(lower alkoxy)_(p)-, e.g. methoxy-(ethoxy)_(p), where p        is an integer from 1 up to and including 10, preferably from 1        up to and including 4, and    -   Z is H, halo, hydroxy, lower alkoxy, lower alkoxy-lower alkoxy,        —NR5R5′, —N⁺R5R5′R5″, —COOH, imidazolyl, optionally R5        substituted -piperazinyl, —CH(COOH)₂, —SO₃ ⁻,        —NR5-(CH₂)_(n)—CH₂—NR5R5′, —NR5-(CH₂)_(n)—CH₂—OR5, morpholino or        tetrahydropyranyl,    -   where R5, R5′ and R5″ are independently H or optionally        substituted (lower alkyl, lower alkoxy-lower alkyl or aryl lower        alkyl, e.g. indolylethyl), or R5, R5′ or R5″ may be linked        together in an optionally substituted N-heterocyclic ring        containing from 3 to 8 ring atoms one or more of which may        comprise a further heteroatom selected from O, S or —NR5-,        wherein R5 is as defined above.

R3 as optionally substituted (aryl-C₂-C₈-alkyl) may be carbocyclicaryl-C₂-C₈-alkyl, e.g. phenyl-C₂-C₈-alkyl, or hetrocyclicaryl-C₂-C₈-alkyl, e.g. pyridyl-C₂-C₈-alkyl, all optionally substituted.

R3 as optionally substituted (aryl-C₂-C₈-alkyl) may be arylethyl, arylpropyl, arylbutyl etc, e.g. phenylethyl or pyridylethyl, all optionallysubstituted.

R3 as optionally substituted (aryl-C₂-C₈-alkenyl) may be carbocyclicaryl-C₂-C₈-alkenyl, e.g. phenyl-C₂-C₈-alkenyl, or heterocyclicaryl-C₂-C₈-alkenyl, e.g. pyridyl-C₂-C₈-alkenyl, all optionallysubstituted.

R3 as optionally substituted (aryl-C₂-C₈-alkenyl) may be arylvinyl,arylpropenyl, arylbutenyl etc, e.g. styryl or pyridylvinyl, alloptionally substituted.

R3 as optionally substituted (aryl-C₂-C₈-alkyl and aryl-C₂-C₈-alkenyl)may be substituted on the aryl ring preferably by 1, 2 or 3 substituentsindependently selected from halogen, nitro, cyano, amino, OH, SH, loweralkyl, lower alkoxy, lower alkyl-SO_(z)—(CH₂)_(y)—O_(x)—, wherein x is 0or 1, y is 0, 1 or 2 and z is 0, 1 or 2, or —X-A-Z, HO-(loweralkoxy)_(p)- or lower alkoxy-(lower alkoxy)_(p) as defined above.

R3 as optionally substituted (aryl-C₂-C₈-alkyl and aryl-C₂-C₈-alkenyl)is optionally substituted on the C₂-C₈-alkyl or on the C₂-C₈-alkenyl by1 to 6, preferably 1, 2 or 3 substituents independently selected fromhalogen, nitro, cyano, amino, OH, SH, lower alkyl, lower alkoxy, loweralkyl-SO_(z)—(CH₂)_(y)—O_(x)—, wherein x is 0 or 1, y is 0, 1 or 2 and zis 0, 1 or 2, or —X-A-Z, HO-(lower alkoxy)_(p)- or lower alkoxy-(loweralkoxy)_(p) as defined above. For example, when C₂-C₈-alkyl is ethyl, itmay be substituted, e.g. at the 2-position, preferably by 1 or 2substituents independently selected from halogen, OH, lower alkyl, e.g.methyl, or lower alkoxy, e.g. methoxy.

R3 as heteroarylmethyl is preferably pyridinylmethyl, e.g.pyridin-2-ylmethyl, pyridin-3-ylmethyl or pyridin-4-ylmethyl,imidazolylmethyl, e.g. imidazol-4-ylmethyl, quinoxalinylmethyl, e.g.quinoxalin-6-ylmethyl, triphenylmethyl, e.g. thiophen-2-ylmethyl,pyrazolylmethyl, e.g. pyrazol-3-ylmethyl, pyrimidinylmethyl, e.g.pyrimidin-5-ylmethyl, indolylmethyl, or furanylmethyl, e.g.furan-2-ylmethyl.

R3 as heteroarylmethyl is optionally substituted on the heteroaryl ringpreferably by 1, 2 or 3 substituents independently selected fromhalogen, nitro, cyano, amino (optionally substituted by lower alkyl),OH, SH, lower alkyl (optionally substituted by halogen, nitro, amino, OHor SH), lower alkoxy, lower thioalkoxy, hydroxy-lower alkoxy, loweralkoxy-lower alkoxy, hydroxy-lower alkoxy-lower alkoxy or aryl, or—X-A-Z, HO-(lower alkoxy)_(p)- or lower alkoxy-(lower alkoxy)_(p) asdefined above.

R3 as 4-heteroarylbenzyl may comprise 4-pyrazinylbenzyl, e.g.4-pyrazin-2-ylbenzyl, or 4-triazolylbenzyl, e.g.4-(1,2,3)triazol-2-ylbenzyl.

Accordingly in particular embodiments the invention provides a compoundof formula I′

wherein Y is O or S;

R1 and R2 are as defined above for formula I;

R3′ is

-   -   A) lower alkyl substituted by 1 to 3 substituents independently        selected from —S-lower alkyl, lower alkylene, cycloalkyl, Br, F        or CF₃; or    -   B) benzyl which is        -   a. mono- or di- (preferably mono-) substituted by            —O_(x)—(CH₂)_(y)—SO_(z)-lower alkyl, wherein x is 0 or 1, y            is 0, 1 or 2 and z is 0, 1 or 2,        -   b. substituted by 1 or 2 substituents selected from            morpholino-lower alkoxy, aryl-lower alkoxy, optionally            N-lower alkyl substituted arylamino-alkoxy,        -   c. substituted at the 2-position by lower alkoxy-,            hydroxy-lower alkoxy- or lower alkoxy-lower alkoxy, or    -   C) optionally substituted (arylvinyl, arylethyl,        heteroarylmethyl or 4-heteroarylbenzyl); or

when R1 is 2 substituents one of which is OH, preferably at the6-position, and the other of which is optionally substituted (loweralkyl or lower alkenyl), preferably at the 5-position, R3′ is H oroptionally substituted (lower alkyl, aryl, aryl-lower alkyl,arylcycloalkyl, cycloalkyl-lower alkyl, cycloalkenyl-lower alkyl,hetereoaryl-lower alkyl, hetereoaryl, or carbonyl lower alkyl); or

when R1 is 2-propynyl and R2 is isopropyl, R3′ is also benzyl which issubstituted by 1 to 3 substituents selected from lower alkyl, loweralkoxy, halo, halo-lower alkyl, e.g. CF₃, —O—CH(H or lower alkyl)-COO(Hor lower alkyl); or

when R1 is 2-propynyl and R2 is isopropyl, R3′ is also benzyl which issubstituted by OH and a second and optionally third substituent selectedfrom lower alkyl, lower alkoxy, halo, —O—CH(H or lower alkyl)-COO(H orlower alkyl); or

when R1 is 2-propynyl and R2 is cyclopropyl, R3′ is also optionallysubstituted benzyl (preferably R3 is also benzyl which is substituted by1 to 3 substituents selected from lower alkyl, lower alkoxy, halo,—O—CH(H or lower alkyl)-COO(H or lower alkyl)); or

when X is S and R1 is as defined above but not methoxy, R3′ is alsooptionally substituted benzyl; or

a compound selected from4-(4-isopropyl-phenyl)-1-(3,4-diamino-benzyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one,1-(2,6-dichloro-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one,1-benzyl-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline-2-thione;1-(3di-tert-butyl-4-hydroxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one,or1-[3-(2-hydroxy-ethoxy)-benzyl]-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline-2-thione;or

a pharmaceutically-acceptable and -cleavable ester, or acid additionsalt thereof; and

provided that when Y is O and R3′ is lower alkyl or cycloalkyl, R3′ isnot isopropyl or cyclopentyl; or

provided the compound of formula I′ is not4-(4isopropyl-phenyl)-6-methoxy-1-pyridin-3-ylmethyl-1.H.-quinazolin-2-one,4-(4-isopropyl-phenyl)-6-methoxy-1-pyridin-2-ylmethyl-1.H.-quinazolin-2-one,1-(6-chloro-pyridin-3-ylmethyl)-4-(4-isopropyl-phenyl)-6-methoxy-1.H.-quinazolin-2-one,4-(4-isopropyl-phenyl)-6-methoxy-1-(5-nitro-furan-2-ylmethyl)-1.H.-quinazolin-2-oneor1-[2-(1.H.-indol-2-yl)-ethyl]-4-(4-isopropyl-phenyl)-6-methoxy-1.H.-quinazolin-2-one,4-(4-isopropyl-phenyl)-6-methoxy-1-phenethyl-1H-quinazolin-2-one,1-(2hydroxy-2-phenyl-ethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one,methanesulfonic acid2-[4-(4-isopropyl-phenyl)-2-oxo-6-prop-2-ynyloxy-2H-quinazolin-1-ylmethyl]-phenylester, or acetic acid2-[4-(4-isopropyl-phenyl)-2-oxo-6-prop-2-ynyloxy-2H-quinazolin-1-yl]-1-phenyl-ethylester,5-allyl-6-hydroxy-1-isopropyl-4-(4-isopropyl-phenyl)-1.H.-quinazolin-2-one,1-cyclopropylmethyl-4-(o-tolyl)-6-nitro-2(1H)-quinazolinone,1-Ethyl-4-(o-tolyl)-6-chloro-2(1H)-quinazolinone,1-cyclopropylmethyl-4-(o-tolyl)-6-chloro-2(1H)-quinazolinone,1-cyclopropylmethyl-4-(o-fluorophenyl)-6-chloro-2(1H)-quinazolinone,1-cyclopropylmethyl-4-(m-chlorophenyl)-6-chloro-2(1H)-quinazolinone,1-cyclopropylmethyl-4-(o-chlorophenyl)-6-nitro-2(1H)-quinazolinone.

Accordingly in particular embodiments the invention further provides acompound of formula I″

wherein Y is O or S;

R1″ is 2 substituents one of which is OH, preferably at the 6-position,and the other of which is optionally substituted (lower alkyl or loweralkenyl), preferably at the 5-position; or R1″ is 2-propynyloxy,preferably at the 6-position;

R2″ is isopropyl, tert. butyl or cyclopropyl;

R3″ is benzyl which is substituted by 1 to 3 substituents selected fromlower alkyl, lower alkoxy, halo, halo-lower alkyl, e.g. CF₃, —CH(H orlower alkyl)-COO(H or lower alkyl); —COO(H or lower alkyl); or

R3″ is benzyl which is substituted by OH and a second and optionallythird substituent selected from lower alkyl, lower alkoxy, halo, —CH(Hor lower alkyl)-COO(H or lower alkyl); or

when R1″ is 2-propynyl and R2″ is cyclopropyl, R3″ is benzyl which issubstituted by 1 to 3 substituents selected from lower alkyl, loweralkoxy, halo, —CH(H or lower alkyl)-COO(H or lower alkyl)); or

when X is S and R1″ is as defined above but not methoxy, R3″ is alsooptionally substituted benzyl; or

a pharmaceutically-acceptable and -cleavable ester, or acid additionsalt thereof.

Moreover, further embodiments of the invention are provided as acompound of formula I′″

wherein R1′″ is 1 to 2 substituents selected from lower alkoxy, loweralkenoxy, lower alknoxy, lower alkyl, lower alkenyl, lower alkinyl, OHor halo (preferably R1′″ is propynyloxy, preferably at the 6 position);

R2′″ is 1 to 3 substituents selected from halo, lower alkyl or loweralkoxy, provided one substituent is isopropyl, tert. butyl orcyclopropyl;

R4′″ is optionally substituted (aryl-lower alkyl, aryl, hetereoaryl,hetereoaryl-lower alkyl, lower alkyl, cycloalkyl, cycloalkyl-loweralkyl, lower alkenyl, lower alkynyl); or

a pharmaceutically-acceptable and -cleavable ester, or acid additionsalt thereof;

provided that the compound of formula I′″ is not4-(4-isopropyl-phenyl)-2-isopropylsulfanyl-6,7-dimethyoxy-quinazoline.

As hereinafter described compounds of formula I may be prepared bycyclisation of a compound of formula II

wherein R1, R2 and R3 are as defined above. Compounds of formula II haveactivity as promoters of PTH release and are included within the presentinvention, e.g. for use as PTH release promoters.

As hereinafter described compounds of formula I′ may be prepared bycyclisation of a compound of formula II′

wherein R1, R2 and R3′ are as defined above. Compounds of formula II′have activity as promoters of PTH release and are included within thepresent invention, e.g. for use as PTH release promoters.

As hereinafter described compounds of formula I″ may be prepared bycyclisation of a compound of formula II″

wherein R1″, R2″ and R3″ are as defined above. Compounds of formula II″have activity as promoters of PTH release and are included within thepresent invention, e.g. for use as PTH release promoters.

As hereinafter described compounds of formula I′″ may be prepared byreaction of a compound of formula I′″ a

wherein R1′″ and R3′″ are as defined above, with HS—R4′″, wherein R4′″is as defined above.

Alternatively, the compounds of formula I′″ may be prepared by reactionof formula II′″b

wherein R1′″ and R2′″ are as defined above,

with Halo-R4′″, wherein R4′″ is as defined above.

Compounds of formula I′″a or compounds of formula II′″b have activity aspromoters of PTH release and are included within the present invention,e.g. for use as PTH release promoters.

Accordingly in a further aspect the invention provides a compound offormula II

wherein R1, R2 and R3 are as defined above;

provided that the compound of formula II is not{2-[2-(3,5-dimethoxy-phenyl)-2-methyl-propylamino]-4,5-dimethoxy-phenyl}-(4-isopropyl-phenyl)-methanone,(4-isopropyl-phenyl)-{5-methoxy-2-[(pyridin-3-ylmethyl)-amino]-phenyl}-methanone,(4-isopropyl-phenyl)-{5-methoxy-2-[(pyridin-2-ylmethyl)-amino]-phenyl}-methanone;or

a compound selected from{2-[2-(2-hydroxy-ethoxy)-benzylamino]-5-prop-2-ynyloxy-phenyl}-(4-isopropyl-phenyl)-methanoneor{2-[(2,3-dimethoxy-quinoxalin-6-ylmethyl)-amino]-5-prop-2-ynyloxy-phenyl}-(4-isopropyl-phenyl)-methanone;

or a pharmaceutically-acceptable and -cleavable ester, or acid additionsalt thereof.

Preferred significances for R1, R2 and R3 in formula II are as describedabove for R1, R2 and R3 in formula I.

Particular significances for R3 in formula II include:

Optionally substituted aryl-C₂-C₈-alkyl; for instance, optionallysubstituted phenylethyl, e.g. optionally mono- or di-lower alkoxysubstituted phenylethyl, in which the ethyl is optionally mono- ordi-substituted (e.g. at the 2-position) by halogen, OH, lower alkyl(e.g. methyl) or lower alkoxy (e.g. methoxy);

Optionally substituted heteroarylmethyl; for instance, optionallysubstituted pyridinylmethyl or quinoxalinylmethyl, e.g. optionally mono-or di-disubstituted by halogen, OH, lower alkyl (e.g. methyl), loweralkoxy (e.g. methoxy), hydroxy-lower alkoxy, (e.g. hydroxy-ethoxy) orlower alkoxy-lower alkoxy (e.g. methoxy-ethoxy); and

Benzyl which is substituted at the 2-position by lower alkoxy-,hydroxy-lower alkoxy- or lower alkoxy-lower alkoxy, e.g2-(2-hydroxy-ethoxy)-benzyl.

Accordingly in particular embodiments the invention provides a compoundof formula II′

wherein R1 and R2 are as defined above for formula I;

R′₃ is as defined above for formula I′

provided that the compound of formula II′ is not{2-[2-(3,5-dimethoxy-phenyl)-2-methyl-propylamino]-4,5-diethoxy-phenyl}-(4-isopropyl-phenyl)-methanone,(4-isopropyl-phenyl)-{5-methoxy-2-[(pyridin-3-ylmethyl)-amino]-phenyl}-methanone,(4-isopropyl-phenyl)-{5-methoxy-2-[(pyridin-2-ylmethyl)-amino]-phenyl}-methanone;or

a compound selected from{2-[2-(2-hydroxy-ethoxy)-benzylamino]-5-prop-2-ynyloxy-phenyl}-(4-isopropyl-phenyl)-methanoneor{2-[(2,3-dimethoxy-quinoxalin-6-ylmethyl)-amino]-5-prop-2-ynyloxy-phenyl}-(4-isopropyl-phenyl)-methanone;

or a pharmaceutically-acceptable and -cleavable ester, or acid additionsalt thereof.

The substituents and optional substituents on R3′ are as described abovefor the optional substituents on R3, including the preferredsignificances thereof.

In particular the invention includes the compounds of formula I andformula II as hereinafter described in the Examples, orpharmaceutically-acceptable and -cleavable esters, or acid additionsalts thereof.

The compounds of formula I and II, and salts and esters thereof, inparticular as identified in the Examples are hereinafter referred to asAgents of the Invention.

The Agents of the Invention which comprise free hydroxyl groups may bealso used in the form of pharmaceutically acceptable, physiologicallycleavable esters, and as such and where novel are included within thescope of the invention. Such pharmaceutically acceptable esters arepreferably prodrug ester derivatives, such being convertible bysolvolysis or cleavage under physiological conditions to thecorresponding Agents of the Invention which comprise free hydroxylgroups. Suitable pharmaceutically acceptable prodrug esters are thosederived from a carboxylic acid, a carbonic acid monoester or a carbamicacid, advantageously esters derived from an optionally substituted loweralkanoic acid or an azylcarboxylic acid.

Agents of the Invention may also exist in the form of pharmaceuticallyacceptable salts, and as such and where novel are included within thescope of the invention.

Pharmaceutically acceptable salts include acid addition salts withconventional acids, for example, mineral acids, e.g., hydrochloric acid,sulfuric or phosphoric acid, or organic acids, for example, aliphatic oraromatic carboxylic or sulfonic acids, e.g., acetic, trifluoroacetic,propionic, succinic, glycolic, lactic, malic, tartaric, citric,ascorbic, maleic, fumaric, hydroxymaleic, pyruvic, pamoic,methanesulfonic, toluenesulfonic, naphthalenesulfonic, sulfanilic orcyclohexylsulfamic acid; also amino acids, such as arginine and lysine.For compounds of the invention having acidic groups, for example, a freecarboxy group, pharmaceutically acceptable salts also represent metal orammonium salts, such as alkali metal or alkaline earth metal salts,e.g., sodium, potassium, magnesium or calcium salts, as well as ammoniumsalts, which are formed with ammonia or suitable organic amines.

Agents of the Invention of formula I and II may be prepared as follows:

Agents of the Invention of Formula I

wherein R1, R2 and R3 are as defined above may be prepared by cyclisinga compound of formula II

with a condensation reagent such as chlorosulfonyl isocyanate(ClSO₂NCO), sodium cyanate, benzoyl isothiocyanate in THF, followed bytreatment with K₂CO₃/methanol or sodium thiocyanate and acetic acid, andthereafter, if required converting the R1, R2 or R3 residues into analternative R1, R2 or R3 residues to give alternative compound offormula II. For example, in the cyclisation reaction the benzophenone offormula II in solution is treated with a solution of sodium cyanate,e.g. in acetic acid at room temperature.

Benzophenone Compounds of Formula II May be Prepared by Treatment of theCorresponding Amine of Formula X

with the corresponding halide, e.g. bromide, R3Br and a suitable basesuch as K₂CO₃. In particular, compounds of formula X where R1 is OH in 6position and R1 is also 2-propenyl, cyclopropyl-methyl or propyl may beprepared as e.g. described in Example for compound5-allyl-1-benzyl-6-hydroxy-4-(4-isopropyl-phenyl)-1H-quinazolin-2-oneand following.

Alternatively, compounds of formula II may be prepared by reductiveamination of the corresponding aldehyde with the amine X, using Ti(Oi-pr)₄ or molecular sieves as dehydrating agent and NaBH(OAc)₃ orNaCNBH₃ as the reducing agent. The amine X is obtainable from thecorresponding nitro derivative (see below compound of formula XI) byreduction, e.g. with iron in acetic acid.

wherein R2 is as previously defined and R1 is an activating group.

The compound of formula XI may in turn be obtained by the oxidation,e.g. with Jones reagent, of the corresponding alcohol which may in turnbe obtained by coupling an organometallic compound derived from thecorresponding bromide of formula XIII and aldehyde of formulae XIIrespectively; for instance as described in the Examples

In a further alternative, compounds of formula II, in particular whereR3 is substituted pyridyl-methyl, may be prepared by reacting thecorresponding alcohol, R3-OH, e.g. pyridyl-methyl-hydroxide, with thecorresponding amine of formula X, e.g. in the presence of Hünig's baseand mesyl chloride; for instance as hereinafter described in theExamples.

In a yet further alternative Agents of the Invention of formula II, inwhich R3 is optionally substituted aryl-lower alkyl may be prepared byalkylation of an Agent of the Invention of formula XX

at the 1-position with the corresponding optionally substitutedaryl-lower alkylhalide; for instance, in the presence of e.g. LiHMDS andNaI, in solution, e.g. THF/DMF, with mild heating.

Alternatively Compounds of Formula XXII

wherein Rx is halo, lower alkyl or lower alkoxy;

may be prepared by reacting a compound of formula XX with thecorresponding oxirane of formula XXI

Where Rx is the optional substitution on the phenyl ring; for instancein the presence of benzyltriethylammonium chloride and potassiumcarbonate, e.g. as hereinafter described in the Examples. Correspondingcompounds of formula II in which R3 is optionally substituted styryl maybe prepared by treatment of a compound of formula XXII with a reagentsuch as trifluoromethanesulphonic anhydride.

The compound of formula XX may be prepared from the correspondingcompound of formula II in which R3 is H by treatment with a condensationreagent such as sodium cyanate.

Agents of the Invention of formula II may be prepared as intermediatesin the preparation of Agents of the Invention of formula I, e.g. asdescribed above, or as hereinafter described in the Examples.

Accordingly the Invention includes processes for the preparation ofAgents of the Invention of formula I

wherein the symbols are as defined above comprising

a) cyclising a compound of formula II

with a condensation reagent such as chlorosulfonyl isocyanate (ClSO₂NCO)or sodium cyanate or sodium thiocyanate; or

b) for an Agent of the Invention of formula I, in which R3 is optionallysubstituted aryl-lower alkyl, alkylation of a compound of formula XX

at the 1-position with the corresponding optionally substitutedaryl-lower alkylhalide; and thereafter, if required converting the R1,R2 or R3 residues into alternative R1, R2 or R3 residues to give analternative compound of formula I.

The preparation of Agents of the Invention of formula II as describedabove is also included within the invention.

Accordingly in a further aspect the invention provides processes for thepreparation of Agents of the Invention of formula II

wherein R1, R2 and R3 are as defined above comprising alkylation of thecorresponding aminobenzophenone compound of formula X

wherein R1 and R2 are as defined above, and thereafter, if required,converting R1, R2 or R3 residues into alternative R1, R2 or R3 residuesto give an alternative compound of formula II.

The invention is described by way of illustration only in the followingnon-limiting Examples which relate to the preparation of compounds ofthe invention of formulae I and II.

EXAMPLES Example 11-(2,3-Dimethoxy-quinoxalin-6-ylmethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

A. Synthesis of{2-[(2,3-dimethoxy-quinoxalin-6-ylmethyl)-amino]-5-prop-2-ynyloxy-phenyl}-(4isopropyl-phenyl)-methanone

To a solution of 82 mg (0.280 mmol)(2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone in 3 mldioxane is added 193 mg (1.40 mmol) potassium carbonate and 119 mg(0.419 mmol) 6-Bromomethyl-2,3-dimethoxy-quinoxaline. The mixture isstirred at 80° C. for two days, diluted with water and extracted withCH₂Cl₂. Purification of the crude product by chromatography (ethylacetate/hexanes 1:1) affords a yellow oil.

¹H NMR (300 MHz, CDCl₃): 7.04-7.60 (m, 10H), 4.94 (s, 2H), 4.52 (d, 2H),4.26 (s, 3H), 4.08 (s, 3H), 2.96 (hept, 1H), 2.48 (t, 1H), 1.28 (d, 6H).

MS: 496 (M+1)⁺

B. Synthesis of1-(2,3-dimethoxy-quinoxalin-6-ylmethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

To a solution of 52 mg (0.105 mmol){2-[(2,3-dimethoxy-quinoxalin-6-ylmethyl)-amino]-5-prop-2-ynyloxy-phenyl}-(4isopropyl-phenyl)-methanonein 1 ml acetic acid is added 14 mg (0.210 mmol) sodium cyanate. Afterstirring for 2 h the solvent is removed in vacuo and the residue ispartitioned between CH₂Cl₂ and water. The organic layer is extractedwith 2 M sodium hydroxide and evaporated. Purification of the crudeproduct by flash-chromatography (ethyl acetate/hexanes 9:1) affords ayellow oil.

¹H NMR (300 MHz, CDCl₃): 7.78 (d, 2H), 7.70 (d, 1H), 7.48 (d, 1H),7.14-7.51 (m, 6H), 6.10 (s, 2H), 4.62 (d, 2H), 4.24 (s, 3H), 4.18 (s,3H), 3.01 (hept, 1H), 2.52 (m, 1H), 1.32 (d, 6H).

MS: 521 (M+1)⁺

The (2-amino-5-propargyloxy-phenyl)-(4isopropyl-phenyl)-methanonebuilding block is prepared as follows:

A. Synthesis of 2-nitro-5-propargyloxy-benzaldehyde

A mixture of 25 g (150 mmol) 5-hydroxy-2-nitro-benzaldehyde, 44.9 g (299mmol) sodium iodide, 44.5 g propargyl bromide (80% in toluene), 42 mlN-ethyl-diisopropy-lamine and 400 ml acetone is stirred at rt for 6 d.The reaction mixture is filtered, concentrated, taken up in 1M aqueoushydrochloric acid and extracted with ethyl acetate to yield2-nitro-5-propargyloxy-benzaldehyde.

¹H NMR (300 MHz, CDCl₃): 10.49 (s, 1H), 8.19 (d, 1H), 7.43 (s, 1H), 7.25(d, 2H), 4.85 (s, 2H), 2.60 (s, 1H).

B. Synthesis of(4-isopropyl-phenyl)-(2-nitro-5-propargyloxy-phenyl)-methanol

To a solution of 30.7 g (150 mmol) 2-nitro-5-propargyloxy-benzaldehydein 200 ml THF are added at −75° C. during 40 min 200 ml (175 mmol) of a0.88 M solution of 4-isopropyl magnesium bromide in THF. After stirringfor 1 h at −75° C. saturated aqueous ammonium chloride solution is addedand the reaction mixture is extracted with portions of ethyl acetate.Evaporation of the organic phases yields(4-isopropyl-phenyl)-(2-nitro-5-propargyloxy-phenyl)-methanol.

¹H NMR (300 MHz, CDCl₃): 8.09 (d, 1H), 7.45 (d, 1H), 7.26 (d, 2H), 7.19(d, 2H), 6.98 (dd, 1H), 6.52 (broad, 1H), 4.80 (d, 2H), 2.88 (hept, 1H),2.71 (broad, 1H), 2.56 (t, 1H), 1.23 (d, 6H).

MS: 308 (100) (M-OH)⁺, 294 (50)

C. Synthesis of(4-isopropyl-phenyl)-(2-nitro-5-propargyloxy-phenyl)-methanone

To an ice cold solution of(4-isopropyl-phenyl)-(2-nitro-5-propargyloxy-phenyl)-methanol in 200 mlacetone are added dropwise 60 ml Jones reagent. After stirring for 2 hat rt the reaction is quenched by the addition of isopropanol and sodiumbisulphite solution (40%). Extraction with dichloromethane affords(4-isopropyl-phenyl)-(2-nitro-5-propargyloxy-phenyl)-methanone.

¹H NMR (300 MHz, CDCl₃): 8.27 (d, 1H), 7.70 (d, 2H), 7.30 (d, 2H), 7.18(dd, 1H), 6.97 (d, 1H), 4.81 (d, 2H), 2.96 (hept, 1H), 2.59 (t, 1H),1.27 (d, 6H).

D. Synthesis of(2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone

To a solution of 10.59 g (30.7 mmol)(4-isopropyl-phenyl)-(2-nitro-5-propargyloxy-phenyl)-methanone in 250 mlacetic acid are added 13.6 g (246 mmol) iron powder. After stirring for20 h at rt the reaction mixture is basified by the addition of 2M sodiumhydroxide solution, filtered and extracted with dichloromethane. Aiderpurification by chromatography using hexanes/ethyl acetate (7:3) aseluent (2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone isobtained.

¹H NMR (300 MHz, CDCl₃): 7.64 (d, 2H), 7.30 (d, 2H), 7.12 (s, 1H), 7.05(d, 1H), 6.72 (d, 1H), 5.71 (broad, 2H), 4.64 (s, 2H), 2.98 (hept, 1H),2.48 (s, 1H), 1.30 (d, 6H).

MS: 294 (M+1)⁺

The (2-amino-4,5-dimethoxy-phenyl)-(4-isopropyl-phenyl)-methanonebuilding block is synthesised following the procedure outlinedimmediately above.

Example 24-(4-Isopropyl-phenyl)-1-(3-methane-sulphonyl-benzyl)-5-propargyloxy-phenyl-methanone

A mixture of 100 mg (0.34 mmol)(2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone, 80 mg(0.58 mmol) K₂CO₃ and 77 mg (0.375 mmol)1-chloro-methyl-3-methanesulphonyl-benzene in 1 ml dimethylformamide isstirred at 80° C. for 6 h and at 100° C. for 3 h. Then the reactionmixture is poured onto water and extracted with ethyl acetate. Thecombined organic layers are washed with water and brine, dried overMgSO₄, filtered and concentrated in vacuo. The residue is purified byflash-chromatography on silica gel (hexane:EtOAc=2:1) to afford thetitle compound as a yellow foam.

¹H-NMR (300 MHz, DMSO): 8.34 (t, 1H), 7.90 (s, 1H), 7.80 (d, 1H), 7.67(d, 1H), 7.60-7.56 (m, 3H), 7.39 (m, 2H), 7.09 (dd, 1H), 7.01 (d, 1H),6.70 (d, 1H), 4.61-4.53 (m, 4H), 3.54 (m, 1H), 3.19 (s, 3H), 2.96 (m,1H), 1.25 (d, 6H).

MS: 462 (M+1)⁺

The starting materials may be prepared as follows:

A. Synthesis of 1-chloromethyl-3-methanesulphonyl-benzene

0.267 ml (3.45 mmol) methanesulphonyl-chloride is added to o a solutionof 584 mg (3.14 mmol) (3-methanesulphonyl-phenyl)-methanol and 0.66 ml(4.71 mmol) triethylamine in 6 ml dichloromethane. This reaction mixtureis stirred at room temperature for 1 h and at 50° C. for additional 3 h.The reaction mixture is then poured into water and extracted twice withdichloromethane. The combined organic layers are washed with water andbrine, dried, filtered and concentrated in vacuo to afford the titlecompound, which is used in the next step without further purification.

¹H-NMR (300 MHz, DMSO): 7.98 (broad s, 1H), 7.86 (d, 1H), 7.77 (d, 2H),7.64 (t, 1H), 4.86 (s, 2H), 3.21 (s, 3H).

B. Synthesis of (3-methanesulphonyl-phenyl)-methanol

NaBH₄ is added to a solution of 750 mg (4.08 mmol)3-methanesulphonyl-benzaldehyde in 20 ml ethanol (see P. L. Ornstein, T.J. Bleisch, M. B. Arnold, R. A. Wright, B. G. Johnson, J. P. Tizzano, D.R. Helton, M. J. Kallman, D. D. Schoepp, M. Herin, J. Med. Chem. 1998,41(3), 358-378 or B. Eistert, W. Schade, H. Selzer, Ber. 1964, 97(5),1470-81). The reaction mixture is stirred at room temperature for 1 h.The reaction mixture is poured into water and extracted three times withethyl acetate. The combined organic layers are washed with water andbrine, dried, filtered and concentrated in vacuo to afford the titlecompound, used in the next step without further purification.

¹H-NMR (300 MHz, DMSO): 7.85 (broad s, 1H), 7.78 (d, 1H), 7.62 (d, 2H),7.59 (t, 1H), 5.45 (t, 3H), 4.58 (d, 2H), 3.19 (s, 3H).

Example 34-(4-Isopropyl-phenyl)-1-(3-methane-sulphonyl-benzyl)-6-propargyloxy-1H-quinazoline-2-one

A mixture of 97 mg (0.21 mmol)4-(4-isopropyl-phenyl)-1-(3-methane-sulphonyl-benzyl)-5-propargyloxy-phenyl-methanoneand 17 mg (0.25 mmol) sodium cyanate in 3 ml acetic acid is stirred atroom temperature for 72 h. Then the reaction mixture is poured intowater and extracted with ethyl acetate. The combined organic layers arewashed with water and brine, dried over MgSO₄, filtered and concentratedin vacuo. The residue is purified by flash-chromatography on silica gel(hexane:EtOAc 1:3) to afford the title compound as a yellow foam.

¹H-NMR (300 MHz, DMSO): 7.95 (s, 1H), 7.81 (d, 1H), 7.70 (d, 2H),7.61-7.50 (m, 2H), 7.47 (m, 2H), 7.45 (d, 2H), 7.38 (m, 1H), 5.59 (broads, 2H), 4.78 (d, 2H), 3.64 (m, 1H), 3.20 (s, 3H), 3.00 (m, 1H), 1.25 (d,6H).

MS: 487 (M+1)⁺

Example 44-(4-Isopropyl-phenyl)-1-[3-(2-methanesulphinyl-ethoxy)-benzyl]-6-prop-2-ynyloxy-1H-quinazolin-2-one

A. Synthesis of 3-(2-methylsulphanyl-ethoxy)-benzaldehyde

NaH (1.3 g, 54 mmol) is added to a solution of 5.0 g (41 mmol)3-hydroxybenzaldehyde in 30 ml DMF at 0° C. After stirring for 1 h 4.44ml (45 mmol) 2-chloroethyl methyl sulphide is added. The reactionmixture is warmed to room temperature and stirring is continued for 16h. Then the reaction mixture is poured onto water and extracted withethyl acetate. The combined organic layers are washed with water andbrine, dried over MgSO₄, filtered and concentrated in vacuo. The residueis purified by flash-chromatography on silica gel (hexane/EtOAc=3:1) toafford the title compound as a colorless oil.

¹H-NMR (300 MHz, DMSO-d₆): 9.94 (s, 1H), 7.51 (m, 1H), 7.50 (s, 1H),7.41 (bs, 1H), 7.27 (m, 1H), 4.20 (t, 2H), 2.85 (t, 2H), 2.18 (s, 3H).

B. Synthesis of 3-(2-methanesulphinyl-ethoxy)-benzaldehyde

A solution of 1.6 g (8.15 mmol)3-(2-methylsulphanyl-ethoxy)-benzaldehyde and 1 ml (9.78 mmol) hydrogenperoxide solution in 30 ml acetic acid is stirred for 2 h at roomtemperature. Then the reaction mixture is poured onto 4N NaOH andextracted with ethyl acetate. The combined organic layers are washedwith sodium bisulphite solution, water and brine, dried over MgSO₄,filtered and concentrated in vacuo to afford the title compound as acolorless solid, sufficiently pure for the next step.

¹H-NMR (300 MHz, DMSO-d₆): 9.96 (s, 1H), 7.52 (m, 1H), 7.51 (s, 1H),7.46 (bs, 1H), 7.30 (m, 1H), 4.40 (m, 2H), 3.26 and 3.08 (m, 2H), 2.62(s, 3H).

MS: 213 (M+1)⁺

C. Synthesis of [3-(2-methanesulphinyl-ethoxy)-phenyl]-methanol

To a solution of 1.1 g (5.18 mmol)3-(2-methanesulphinyl-ethoxy)-benzaldehyde in 20 ml ethanol (anhydrous)is added NaBH₄ (0.215 g, 5.7 mmol). The reaction mixture is stirred atroom temperature for 0.5 h. Then it is poured onto water and extractedwith ethyl acetate. The combined organic layers are washed with waterand brine, dried over MgSO₄, filtered and concentrated in vacuo toafford the title compound as a colorless oil that is of sufficientpurity for the next step.

¹H-NMR (300 MHz, DMSO-d₆): 7.20 (t, 1H), 6.90 (bs, 1H), 6.88 (d, 1H),6.80 (d, 1H), 5.18 (t, 1H), 4.45 (d, 2H), 4.30 (m, 2H), 3.25 and 3.04(m, 2H), 2.61 (s, 3H).

D. Synthesis of 1-chloromethyl-3-(2-methanesulphinyl-ethoxy)-benzene

To a solution of 0.7 g (3.27 mmol) and 1.7 ml triethylamine in 30 mldichloromethane MeSO₂Cl (0.315 ml, 4 mmol) is added at 0° C. Thereaction mixture is stirred at 0° C. for 1 h and at room temperature for70 h. After that the reaction mixture is poured onto water and extractedwith ethyl acetate. The combined organic layers are washed with waterand brine, dried over MgSO₄, filtered and concentrated in vacuo. Theresidue is purified by flash-chromatography on silica gel(dichloromethane/MeOH=9:1) to afford the title compound as a colorlessoil.

¹H-NMR (300 MHz, DMSO-d₆): 7.28 (t, 1H), 7.04 (bs, 1H), 7.02 (d, 1H),6.94 (d, 1H), 4.71 (s, 2H), 4.32 (m, 2H), 3.26 and 3.04 (m, 2H), 2.62(s, 3H)

MS: 233 (M+1)⁺

E. Synthesis of(4-isopropyl-phenyl)-{2-[3-(2-methanesulphinyl-ethoxy)-benzylamino]-5-prop-2-ynyloxy-phenyl}-methanone

The title compound is prepared from2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone and1-chloromethyl-3-(2-methanesulphinyl-ethoxy)-benzene as described forthe preparation of example 2.

¹H-NMR (300 MHz, DMSO-d₆): 8.32 (t, 1H), 7.56 (d, 2H), 7.38 (d, 2H),7.24 (t, 1H), 7.10 (dd, 1H), 7.00 (bs, 1H), 6.95 (m, 2H), 6.86 (dd, 1H),6.74 (d, 1H), 4.57 (s, 2H), 4.42 (d, 2H), 4.28 (m, 2H), 3.55 (m, 1H),3.24-3.00 (m, 2H), 3.00 (m, 1H), 2.60 (s, 3H), 1.24 (d, 6H).

MS: 490 (M+1)⁺

F. Synthesis of4-(4-Isopropyl-phenyl)-1-[3-(2-methanesulphinyl-ethoxy)-benzyl]-6-prop-2-ynyloxy-1H-quinazoline-2-one

The title compound (yellow oil) is prepared from(4-isopropyl-phenyl)-{2-[3-(2-methanesulphinyl-ethoxy)-benzylamino]-5-prop-2-ynyloxy-phenyl}-methanoneand sodium cyanate as described for the preparation of example 3.

¹H-NMR (300 MHz, DMSO-d₆): 7.72 (d, 2H), 7.48 (d, 2H), 7.46 (s, 2H),7.35 (bs, 1H), 7.24 (t, 1H), 6.94 (bs, 1H), 6.87 (dd, 1H), 6.81 (d, 1H),5.46 (bs, 2H), 4.79 (s, 2H), 4.30 (m, 2H), 3.67 (m, 1H), 3.24-3.00 (m,2H), 3.02 (m, 1H), 2.61 (s, 3H), 1.29 (d, 6H).

MS: 515 (M+1)⁺

Example 54-(4-Isopropyl-phenyl)-1-[3-(2-methanesulphonyl-ethoxy)-benzyl]-6-prop-2-ynyloxy-1H-quinazoline-2-one

¹H-NMR (300 MHz, DMSO-d₆): 7.66 (d, 2H), 7.46 (d, 2H), 7.44 (s, 2H),7.30 (bs, 1H), 7.20 (t, 1H), 6.95 (bs, 1H), 6.87 (m, 1H), 6.76 (d, 1H),5.42 (s, 2H), 4.75 (s, 2H), 4.27 (t, 2H), 3.63 (m, 1H), 3.56 (t, 2H),3.02 (s, 3H), 3.00 (m, 1H), 1.24 (d, 6H).

MS: 531 (M+1)⁺

1-Chloromethyl-3-(2-methanesulphonyl-ethoxy)-benzene can be preparedfrom 3-(2-methanesulphonyl-ethoxy)-benzaldehyde as described for thepreparation of 1-chloromethyl-3-(2-methanesulphinyl-ethoxy)-benzene(example 4B)

A solution of 2.0 g (10.2 mmol)3-(2-methylsulphanyl-ethoxy)-benzaldehyde and 2.3 ml (22.4 mmol)hydrogen peroxide solution in 10 ml acetic acid is stirred for 2 h at100° C. Then the reaction mixture is poured onto 2N NaOH and extractedwith ethyl acetate. The combined organic layers are washed with sodiumbisulphite solution, water and brine, dried over MgSO₄, filtered andconcentrated in vacuo. The residue is purified by flash-chromatographyon silica gel (hexane/EtOAc=3:1) to afford the title compound as a whitecrystalline compound.

¹H-NMR (300 MHz, DMSO-d₆): 9.96 (s, 1H), 7.54 (2d, 2H), 7.46 (bs, 1H),7.32 (m, 1H), 4.42 (t, 2H), 3.63 (t, 2H), 3.06 (s, 3H)

MS: 229 (M+1)⁺

Example 64-(4-Isopropyl-phenyl)-1-[2-(2-methoxy-ethyl)-2H-tetrazol-5-ylmethyl]-6-prop-2-ynyloxy-1H-quinazolin-2-thione

A. Synthesis of[2-(4-isopropyl-benzoyl)-4-prop-2-ynyloxy-phenylamino]-acetonitrile

A mixture of 2.0 g (6.83 mmol)2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone, 0.516 g(7.5 mmol) chloroacetonitrile and 1.6 g K₂CO₃ in 20 ml DMF is heated to100° C. and stirred at this temperature for 20 h. The reaction mixtureis cooled to room temperature and poured onto water and extracted withethyl acetate. The combined organic layers are washed with water andbrine, dried over MgSO₄, filtered and concentrated in vacuo. The residueis purified by flash-chromatography on silica gel (hexane/EtOAc=3:1) toafford 1.26 g of the title compound as a yellow crystalline solid.

¹H-NMR (300 MHz, DMSO-d₆): 7.60 (m, 1H), 7.60 (d, 2H), 7.40 (d, 2H),7.28 (dd, 1H), 7.04 (bs, 1H), 6.96 (d, 1H), 4.67 (s, 2H), 4.42 (d, 2H),3.59 (s, 1H), 2.98 (m, 1H), 1.25 (d, 6H).

MS: 333 (M+1)⁺

B. Synthesis of(4-isopropyl-phenyl)-{5-prop-2-ynyloxy-2-[(1H-tetrazol-5-ylmethyl)-amino]-phenyl}-methanone

A solution of 0.82 g (2.47 mmol)[2-(4-isopropyl-benzoyl)-4-prop-2-ynyloxy-phenyl-amino]-acetonitrile and0.8 ml (3.31 mmol) Bu₃SnN₃ in 20 ml m-xylene is stirred at refluxtemperature for 5 h. Then the reaction mixture is cooled to roomtemperature and 15 ml 2N KOH and 2 ml MeOH are added. This mixture isstirred vigorously for 15 min. After that the phases are separated andto the water layer 4 N HCl is added until a pH ˜1 is reached. Theaqueous layer is extracted with dichloromethane/isopropanol=3:1. Thecombined organic layers are washed with water and brine, dried overMgSO₄, filtered and concentrated in vacuo. The resulting solid issuspended in diethyl ether, stirred for 0.5 h, filtered and dried toafford 0.89 g of the title compound as yellow crystals.

¹H-NMR (300 MHz, DMSO-d₆): 8.22 (t, 1H), 7.59 (d, 2H), 7.40 (d, 2H),7.14 (dd, 1H), 7.04 (bs, 1H), 6.72 (d, 1H), 4.81 (d, 2H), 4.61 (s, 2H),3.59 (s, 1H), 2.98 (m, 1H), 1.25 (d, 6H).

MS: 376 (M+1)⁺

C. Synthesis of(4-isopropyl-phenyl)-(2-{[2-(2-methoxy-ethyl)-2H-tetrazol-5-ylmethyl]-amino}-5-prop-2-ynyloxy-phenyl)-methanone

A mixture of 1.04 g (2.77 mmol)(4-isopropyl-phenyl)-{5-prop-2-ynyloxy-2-[(1H-tetrazol-5-ylmethyl)-amino]-phenyl}-methanone,0.85 g K₂CO₃, 0.25 g KI and 0.41 g (2.95 mmol) chloroacetonitrile and 40ml ethyl methyl ketone is stirred at 60° C. for 20 h. The reactionmixture is cooled to room temperature and poured onto water andextracted with ethyl acetate. The combined organic layers are washedwith water and brine, dried over MgSO₄, filtered and concentrated invacuo. The residue is purified by flash-chromatography on silica gel(hexane/EtOAc=2:1) to afford 0.65 g of(4-isopropyl-phenyl)-(2-{[2-(2-methoxy-ethyl)-2H-tetrazol-5-ylmethyl]-amino}-5-prop-2-ynyloxy-phenyl)-methanone(yellow oil, title compound) and 0.3 g of(4-isopropyl-phenyl)-(2-{[1-(2-methoxy-ethyl)-1H-tetrazol-5-ylmethyl]-amino}-5-prop-2-ynyloxy-phenyl)-methanone(yellow oil).

¹H-NMR (300 MHz, DMSO-d₆): 8.32 (t, 1H), 7.56 (d, 2H), 7.38 (d, 2H),7.18 (dd, 1H), 7.02 (bs, 1H), 6.92 (d, 1H), 4.78 (t, 2H), 4.72 (d, 2H),4.60 (s, 2H), 3.80 (t, 2H), 3.55 (s, 1H), 3.18 (s, 3H), 2.96 (m, 1H),1.24 (d, 6H).

MS: 434 (M+1)⁺

D. Synthesis of4-(4-isopropyl-phenyl)-1-[2-(2-methoxy-ethyl)-2H-tetrazol-5-ylmethyl]-6-prop-2-ynyloxy-1H-quinazolin-2-thione

The title compound (red foam) is prepared from(4-isopropyl-phenyl)-(2-{[2-(2-methoxy-ethyl)-2H-tetrazol-5-ylmethyl]-amino}-5-prop-2-ynyloxy-phenyl)-methanoneand benzoylisothiocyanate as described for the preparation of example111.

¹H-NMR (300 MHz, DMSO-d₆): 7.74 (d, 2H), 7.73 (d, 1H), 7.60 (dd, 1H),7.48 (d, 2H), 7.41 (m, 1H), 6.40 (bs, 2H), 4.88 (bs, 2H), 4.77 (t, 2H),3.76 (t, 2H), 3.74 (m, 1H), 3.16 (s, 3H), 3.00 (m 1H), 1.28 (d, 6H).

MS: 475 (M+1)⁺

The compounds of the following examples are prepared by analogy:

Example 74-(4-Isopropyl-phenyl)-1-(3-methane-sulphonyl-benzyl)-5-propargyloxy-phenyl-methanone

The title compound can be prepared using the synthesis methodology asdescribed using 1-chloromethyl-3-methanesulphinyl-benzene (see S. A.Laufer, G. K. Wagner J. Med. Chem. 2002, 45(13), 2733-40).

MS: 446 (M+1)⁺

Example 84-(4-Isopropyl-phenyl)-1-(3-methane-sulphinyl-benzyl)-6-propargyloxy-1H-quinazoline-2-one

¹H-NMR (300 MHz, DMSO): 7.70 (d, 2H), 7.66 (s, 1H), 7.58-7.44 (m, 6H),7.39 (broad s, 1H), 7.35 (broad s, 1H), 5.59 (broad s, 2H), 4.78 (d,2H), 3.67 (m, 1H), 3.02 (m, 1H), 2.72 (s, 3H), 1.28 (d, 6H).

MS: 471 (M+1)⁺

Example 94-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-1-pyridin-2-ylmethyl-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 8.58 (d, 1H), 7.76 (d, 2H), 7.20-7.70 (m, 8H),5.68 (s, 2H), 4.64 (d, 2H), 3.02 (hept, 1H), 2.54 (t, 1H), 1.32 (d, 6H).

MS: 410 (M+1)⁺

Example 104-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-1-(4-[1,2,3]triazol-2-yl-benzyl)-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 8.04 (d, 2H), 7.72-7.80 (m, 3H), 7.20-7.52 (m,8H), 5.60 (s, 2H), 4.64 (d, 2H), 3.02 (hept, 1H), 2.55 (m, 1H), 1.33 (d,6H).

MS: 476 (M+1)⁺

Example 111-(3-Bromo-propyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.69 (d, 2H), 7.46-7.53 (m, 3H), 7.37 (d, 2H),4.63 (d, 2H), 4.42 (m, 2H), 3.58 (t, 2H), 2.99 (hept, 1H), 2.58 (m, 1H),2.38 (m, 2H), 1.30 (d, 6H).

MS: 441 (M+1)⁺

Example 124-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-1-pyridin-3-ylmethyl-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 8.78 (s, 1H), 8.58 (d, 1H), 7.90 (d, 1H), 7.74(d, 2H), 7.54 (d, 1H), 7.26-7.44 (m, 5H), 5.60 (s, 2H), 4.64 (d, 2H),3.01 (hept, 1H), 2.56 (t, 1H), 1.32 (d, 6H).

MS: 410 (M+1)⁺

Example 131-[2-(2-Hydroxy-ethoxy)-benzyl]-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

A. Synthesis of{2-[2-(2-Hydroxy-ethoxy)-benzylamino]-5-prop-2-ynyloxy-phenyl}-(4-isopropyl-phenyl)-methanone

To a solution of 100 mg (0.341 mmol)(2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone in 1.5 mlCH₂Cl₂ is added 61 mg (0.36 mmol) 2-(2-hydroxyethoxy)benzaldehyde and 84mg (0.38 mmol) sodium triacetoxyborohydride. The mixture is stirred atr.t. for two days, diluted with water and extracted with CH₂Cl₂.Purification of the crude product by chromatography (ethylacetate/hexanes 1:1) affords a yellow solid.

¹H NMR (300 MHz, CD₃OD): 7.56 (d, 2H), 7.34 (d, 2H), 7.16-7.30 (m, 2H),7.06-7.12 (m, 2H), 6.84-7.00 (m, 3H), 4.50-4.54 (m, 4H), 4.12 (t, 2H),3.96 (t, 2H), 3.00 (hept, 1H), 2.92 (t, 1H), 1.32 (d, 6H).

MS: 444 (M+1)⁺

B. Synthesis of1-[2-(2-Hydroxy-ethoxy)-benzyl]-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

To a solution of 85 mg (0.192 mmol){2-[2-(2-Hydroxy-ethoxy)-benzylamino]-5-prop-2-ynyloxy-phenyl}-(4-isopropyl-phenyl)-methanonein 2 ml acetic acid is added 25 mg (0.383 mmol) sodium cyanate. Afterstirring for 2 h the solvent is removed in vacuo and the residue ispartitioned between CH₂Cl₂ and water. The organic layer is extractedwith 2 M sodium hydroxide solution. After evaporation of the organicphase the product is obtained as a yellow oil.

¹H NMR (300 MHz, CDCl₃): 7.76 (d, 2H), 7.20-7.56 (m, 6H), 6.94 (t, 1H),6.86 (d, 1H), 5.62 (s, 2H), 4.04 (t, 2H), 3.94 (t, 2H), 3.02 (hept, 1H),2.56 (m, 1H), 1.32 (d, 6H).

MS: 469 (M+1)⁺

Example 141-[3-(2-Hydroxy-ethoxy)-thiophen-2-ylmethyl]-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H-NMR (300 MHz, CDCl₃): 7.64-7.84 (m, 3H), 7.22-7.50 (m, 4H), 7.12 (d,1H), 6.76 (d, 1H), 5.58 (s, 2H), 4.62 (d, 2H), 4.20 (t, 2H), 3.96 (t,2H), 3.42 (broad s, 1H), 3.00 (hept, 1H), 2.54 (t, 1H), 1.30 (d, 6H).

MS: 475 (M+1)⁺

The starting material may be prepared as follows:

A. Synthesis of 2-(thiophen-3-yloxy)-ethanol

To a solution of 1.0 g (4.76 mmol) 3-iodothiophene in 5 ml ethyleneglycol is added 109 mg (1.71 mmol) copper powder, 114 mg (0.714 mmol)copper(II)sulphate and 151 mg (19.0 mmol) lithium hydride. The reactionmixture is heated overnight in a sealed flask at 100° C. The reactionmixture is filtered through Celite and evaporated. The resulting oil isthen filtered through a 50 g silica pad and eluted with ethylacetate/hexanes (7:3) to give after evaporation 750 mg of an orangeliquid, which is used without purification directly in the nextreaction.

HPLC-MS: t=1.31 min. ((M+1)⁺=145)

B. Synthesis of 3-(2-hydroxy-ethoxy)-thiophene-2-carboxaldehyde

The crude material (750 mg) obtained in the reaction above is addeddropwise at 0° C. to a mixture of 1.15 ml (8.32 mmol) diphosphorylchloride and 1 ml (13 mmol) DMF. The reaction mixture is stirred for twohours at room temperature. 50 ml of cold 2N NaHCO₃ solution are addedand the resulting mixture is extracted with dichloromethane, dried,filtered through Celite and evaporated in vacuo. Flash-chromatography(hexanes/ethyl acetate) gives a yellow oil, which is used withoutfurther purification in the reductive amination reaction.

Example 151-(3-Chloro-4-hydroxy-5-methoxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

A. Synthesis of[2-(3-chloro-4-hydroxy-5-methoxy-benzylamino)-5-prop-2-ynyloxy-phenyl]-(4-isopropyl-phenyl)-methanone

To a stirred mixture of 146.7 mg (0.5 mmol) of(2-amino-5-prop-2-ynyloxy-phenyl)-4-isopropyl-phenyl)-methanone and 28.6μl (0.5 mmol) of acetic acid in 1.5 ml of methanol is added 93.3 mg (0.5mmol) of 5-chlorovanillin followed by 31.4 mg (0.5 mmol) of sodiumcyanoborohydride. After stirring for 40 h at r.t., the reaction isquenched with 1N HCl and subsequently made alkaline with 1N aqueous NaOHsolution. Methanol is removed in vacuo, the residue diluted with waterand extracted twice with ethyl acetate. The combined organic layers aredried (Na₂SO₄) and evaporated. Flash chromatography of the residue(SiO₂, hexane/ethyl acetate) affords the title compound as a yellowsolid.

¹H-NMR (400 MHz, DMSO-d6): 9.28 (s, 1H), 8.20 (t, 1H), 7.57 (d, 2H),7.40 (d, 2H), 7.13 (dd, 1H), 7.02 (d, 1H), 6.95 (d, 1H), 6.90 (d, 1H),6.76 (d, 1H), 4.59 (d, 2H), 4.34 (d, 2H), 3.77 (s, 3H), 3.54 (t, 1H),2.97 (m, 1H), 1.24 (d, 6H).

MS: 464 (M+1)⁺

B. Synthesis of1-(3-chloro-4-hydroxy-5-methoxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

To a mixture of 43.1 mg (0.093 mmol) of[2-(3-Chloro-4-hydroxy-5-methoxy-benzyl-amino)-5-prop-2-ynyloxy-phenyl]-(4-isopropyl-phenyl)-methanonein 1 ml of acetic acid is added 12.1 mg (0.186 mmol) of sodium cyanate.After stirring for 12 h at r.t. the solvent is removed in vacuo and theresidue partitioned between saturated NaHCO₃ solution and ethyl acetate.The organic layer is separated and the aqueous phase extracted twicewith ethyl acetate. The combined organic extracts are dried (Na₂SO₄) andevaporated in vacuo. Flash chromatography (SiO2, hexane/ethyl acetate)affords the title compound as an amorphous yellow solid.

¹H NMR (400 MHz, DMSO-d6): 9.41 (s, 1H), 7.73 (d, 2H), 7.48-7.58 (m,4H), 7.36 (d, 1H), 7.07 (d, 1H), 6.84 (d, 1H), 5.39 (broad s, 2H), 4.81(d, 2H), 3.81 (s, 3H), 3.68 (t, 1H), 3.03 (m, 1H), 1.29 (d, 6H).

MS: 489 (M+1)⁺

The compounds of the following examples are prepared in an analogousmanner.

Example 161-(2-Ethoxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 7.73 (d, 2H), 7.46-7.50 (m, 3H), 7.37 (d,1H), 7.30 (d, 1H), 7.23 (dt, 1H), 7.06 (d, 1H), 6.76-6.83 (m, 2H), 5.39(broad s, 2H), 4.79 (d, 2H), 4.16 (q, 2H), 3.67 (t, 1H), 3.03 (m, 1H),1.41 (t, 3H), 1.29 (d, 6H).

MS: 453 (M+1)⁺

Example 171-(3-Ethoxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 7.72 (d, 2H), 7.46-7.50 (m, 4H), 7.36 (d,1H), 7.22 (t, 1H), 6.86 (m, 1H), 6.79-6.81 (m, 2H), 5.45 (broad s, 2H),4.78 (d, 2H), 3.97 (q, 2H), 3.66 (t, 1H), 3.02 (m, 1H), 1.26-1.30 (m,9H).

MS: 453 (M+1)⁺

Example 181-(2-Hydroxy-6-methoxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 9.90 (s, 1H), 7.67 (d, 2H), 7.61 (d, 1H),7.40-7.47 (m, 3H), 7.27 (d, 1H), 7.03 (t, 1H), 6.43 (d, 2H), 5.44 (s,2H), 4.75 (d, 2H), 3.65 (s, 3H), 3.63 (t, 1H), 3.00 (m, 1H), 1.27 (d,6H).

MS: 455 (M+1)⁺

Example 191-(3-Ethoxy-4-methoxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 7.71 (d, 2H), 7.47-7.55 (m, 4H), 7.35 (d,1H), 7.05 (s, 1H), 6.86 (d, 1H), 6.73-6.76 (m, 1H), 5.41 (broad s, 2H),4.79 (d, 2H), 3.97 (q, 2H), 3.69 (s, 3H), 3.66 (m, 1H), 3.02 (m, 1H),1.26-1.32 (m, 9H).

MS: 483 (M+1)⁺

Example 201-(1H-Indol-4-ylmethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 11.10 (s, 1H), 7.74 (d, 2H), 7.49 (d, 2H),7.29-7.42 (m, 5H), 6.96 (t, 1H), 6.64 (m, 1H), 6.59 (d, 1H), 5.74 (broads, 2H), 4.76 (d, 2H), 3.65 (t, 1H), 3.03 (m, 1H), 1.29 (d, 6H).

MS: 448 (M+1)⁺

Example 211-(4Hydroxy-3-methoxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 7.70 (d, 2H), 7.56 (d, 1H), 7.45-7.49 (m,3H), 7.34 (d, 1H), 7.03 (d, 1H), 6.61-6.69 (m, 2H), 5.37 (broad s, 2H),4.78 (d, 2H), 3.73 (s, 3H), 3.66 (t, 1H), 3.01 (m, 1H), 1.28 (d, 6H).

MS: 455 (M+1)⁺

Example 221-(2-Hydroxy-4-methoxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 10.05 (broad s, 1H), 7.70 (d, 2H), 7.40-7.50(m, 4H), 7.35 (d, 1H), 6.76 (d, 1H), 6.46 (d, 1H), 6.28 (dd, 1H), 5.29(broad s, 2H), 4.78 (d, 2H), 3.66 (m, 1H), 3.64 (s, 3H), 3.02 (m, 1H),1.28 (d, 6H).

MS: 455 (M+1)⁺

Example 232-Hydroxy-5-[4-(4-isopropyl-phenyl)-2-oxo-6-prop-2-ynyloxy-2H-quinazolin-1-ylmethyl]-benzoicacid methyl ester

¹H NMR (400 MHz, DMSO-d6): 10.44 (s, 1H), 7.82 (d, 1H), 7.71 (d, 2H),7.47-7.56 (m, 5H), 7.35 (d, 1H), 6.95 (d, 1H), 5.44 (broad s, 2H), 4.78(d, 2H), 3.86 (s, 3H), 3.66 (t, 1H), 3.02 (m, 1H), 1.28 (d, 6H).

MS: 483 (M+1)⁺

Example 241-(3-Chloro-4-hydroxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 10.15 (s, 1H), 7.70 (d, 2H), 7.46-7.54 (m,4H), 7.35 (m, 2H), 7.09 (dd, 1H), 6.90 (d, 1H), 5.37 (broad s, 2H), 4.78(d, 2H), 3.66 (t, 1H), 3.02 (m, 1H), 1.28 (d, 6H).

MS: 459 (M+1)⁺

Example 251-(2-Chloro-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 7.74 (d, 2H), 7.56 (dd, 1H), 7.47-7.51 (m,3H), 7.40 (d, 1H), 7.32 (dt, 1H), 7.25 (d, 1H), 7.21 (dt, 1H), 6.81 (dd,1H), 5.48 (broad s, 2H), 4.80 (d, 2H), 3.69 (t, 1H), 3.03 (m, 1H), 1.29(d, 6H).

MS: 443 (M+1)⁺

Example 261-(4-Hydroxy-3,5-dimethoxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 8.34 (s, 1H), 7.71 (d, 2H), 7.59 (d, 1H),7.46-7.50 (m, 3H), 7.35 (d, 1H), 6.66 (s, 2H), 5.37 (broad s, 2H), 4.78(d, 2H), 3.68 (s, 6H), 3.66 (t, 1H), 3.01 (m, 1H), 1.28 (d, 6H).

MS: 485 (M+1)⁺

Example 271-(2,5-Dimethoxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 7.72 (d, 2H), 7.46-7.49 (m, 3H), 7.37 (d,1H), 7.28 (d, 1H), 7.02 (d, 1H), 6.83 (dd, 1H), 6.29 (d, 1H), 5.35(broad s, 2H), 4.78 (d, 2H), 3.87 (s, 3H), 3.67 (t, 1H), 3.56 (s, 3H),3.02 (m, 1H), 1.28 (d, 6H).

MS: 469 (M+1)⁺

Example 284-[4-(4-Isopropyl-phenyl)-2-oxo-6-prop-2-ynyloxy-2H-quinazolin-1-ylmethyl]-1H-indole-2-carboxylicacid amide

¹H NMR (400 MHz, DMSO-d6): 11.50 (s, 1H), 8.03 (broad s, 1H), 7.75 (d,2H), 7.50 (d, 2H), 7.38-7.44 (m, 4H), 7.26-7.32 (m, 2H), 7.04 (t, 1H),6.47 (d, 2H), 5.72 (broad s, 2H), 4.78 (d, 2H), 3.67 (t, 1H), 3.03 (m,1H), 1.29 (d, 6H).

MS: 491 (M+1)⁺

Example 291-(2-Ethyl-butyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 7.68 (d, 2H), 7.55-7.60 (m, 2H), 7.46 (d,2H), 7.34 (d, 1H), 4.80 (d, 2H), 4.20 (d, 2H), 3.69 (t, 1H), 3.01 (m,1H), 1.85 (m, 1H), 1.30-1.38 (m, 4H), 1.28 (d, 6H), 0.87 (t, 6H).

MS: 403 (M+1)⁺

Example 30{3-[4-(4-Isopropyl-phenyl)-2-oxo-6-prop-2-ynyloxy-2H-quinazolin-1-ylmethyl]-phenoxy}-aceticacid

¹H NMR (400 MHz, DMSO-d6): 7.71 (d, 2H), 7.45-7.48 (m, 4H), 7.35 (d,1H), 7.17 (m, 1H), 6.81 (broad s, 1H), 6.69-6.76 (m, 2H), 5.43 (broad s,2H), 4.77 (d, 2H), 4.30 (s, 2H), 3.65 (t, 1H), 3.01 (m, 1H), 1.28 (d,6H).

MS: 483 (M+1)⁺

Example 311-(2,3-Dimethoxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 7.72 (d, 2H), 7.47-7.50 (m, 3H), 7.32-7.37(m, 2H), 6.91-6.98 (m, 2H), 6.41 (dd, 1H), 5.45 (broad s, 2H), 4.78 (d,2H), 3.87 (s, 3H), 3.82 (s, 3H), 3.67 (t, 1H), 3.02 (m, 1H), 1.28 (d,6H).

MS: 469 (M+1)⁺

Example 321-(2,3-Dihydro-benzo[1,4]dioxin-6-ylmethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 7.70 (d, 2H), 7.46-7.51 (m, 4H), 7.35 (d,1H), 6.77-6.82 (m, 3H), 5.37 (broad s, 2H), 4.18 (s, 4H), 3.66 (t, 1H),3.01 (m, 1H), 1.28 (d, 6H).

MS: 467 (M+1)⁺

Example 334-(4-Isopropyl-phenyl)-1-(4-oxo-4H-chromen-3-ylmethyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 8.23 (s, 1H), 8.13 (dd, 1H), 7.82 (dt, 1H),7.70 (d, 2H), 7.62-7.65 (m, 2H), 7.47-7.54 (m, 4H), 7.35 (d, 1H), 5.25(s, 2H), 4.80 (d, 2H), 3.67 (m, 1H), 3.02 (m, 1H), 1.28 (d, 6H).

MS: 477 (M+1)⁺

Example 344-(4-Isopropyl-phenyl)-1-(2-methyl-butyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 7.62-7.68 (m, 3H), 7.53 (dd, 1H), 7.46 (d,2H), 7.33 (d, 1H), 4.80 (d, 2H), 4.14 (m, 2H), 3.68 (t, 1H), 3.00 (m,1H), 1.92-2.01 (m, 1H), 1.37-1.45 (m, 1H), 1.27 (d, 6H), 1.18-1.26 (m,1H), 0.88 (m, 6H).

MS: 389 (M+1)⁺

Example 351-(2,6-Dichloro-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.78 (d, 2H), 7.44 (d, 1H), 7.38 (d, 2H),7.15-7.40 (m, 5H), 5.90 (s, 2H), 4.62 (d, 2H), 3.01 (hept, 1H), 2.55 (m,1H), 1.31 (d, 6H).

MS: 477 (M+1)⁺

Example 361-(2,3-Dichloro-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 7.74 (d, 2H), 7.57-7.60 (m, 1H), 7.46-7.51(m, 3H), 7.40 (d, 1H), 7.31 (d, 1H), 7.23 (t, 1H), 6.76 (d, 1H), 5.49(s, 2H), 4.80 (d, 2H), 3.69 (t, 1H), 3.03 (m, 1H), 1.29 (d, 6H).

MS: 477/479 (M+1)⁺

Example 374-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-1-(3-trifluoromethyl-benzyl)-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 7.78 (s, 1H), 7.72 (d, 2), 7.64 (m, 1H),7.47-7.58 (m, 6H), 7.38 (d, 1H), 5.58 (s, 2H), 4.79 (d, 2H), 3.67 (t,1H), 3.02 (m, 1H), 1.28 (d, 6H).

MS: 477 (M+1)⁺

Example 384-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-1-(4-trifluoromethyl-benzyl)-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 7.71 (m, 4H), 7.43-7.51 (m, 6H), 7.37 (d,1H), 5.59 (broad s, 2H), 4.79 (d, 2H), 3.67 (t, 1H), 3.02 (m, 1H), 1.28(d, 6H).

MS: 477 (M+1)⁺

Example 391-(3-Ethoxy-4-hydroxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 8.86 (s, 1H), 7.70 (d, 2H), 7.46-7.55 (m,4H), 7.33 (d, 1H), 7.00 (s, 1H), 6.63-6.70 (m, 2H), 5.36 (broad s, 2H),4.78 (d, 2H), 3.97 (q, 2H), 3.65 (t, 1H), 3.02 (m, 1H), 1.29 (t, 3H),1.28 (d, 6H).

MS: 469 (M+1)⁺

Example 404-(4-Isopropyl-phenyl)-1-(3-phenyl-butyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 7.63 (d, 2H), 7.50 (dd, 1H), 7.45 (d, 2H),7.37 (d, 1H), 7.28-7.32 (m, 5H), 7.17-7.21 (m, 1H), 4.79 (d, 2H),4.12-4.21 (m, 1H), 3.97-4.04 (m, 1H), 3.68 (t, 1H), 2.91-3.03 (m, 2H),1.86-2.01 (m, 2H), 1.27 (m, 9H).

MS: 451 (M+1)⁺

Example 411-(3,4-Diethoxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 7.70 (d, 2H), 7.46-7.54 (m, 4H), 7.33 (d,1H), 7.04 (d, 1H), 6.84 (d, 1H), 6.71 (dd, 1H), 5.39 (broad s, 2H), 4.78(d, 2H), 3.91-4.00 (m, 4H), 3.65 (t, 1H), 3.01 (m, 1H), 1.25-1.30 (m,12H).

MS: 497 (M+1)⁺

Example 421-(3-Fluoro-4-methoxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 7.71 (d, 2H), 7.47-7.53 (m, 4H), 7.35 (d,1H), 7.24 (dd, 1H), 7.06-7.13 (m, 2H), 5.42 (broad s, 2H), 4.78 (d, 2H),3.78 (s, 3H), 3.67 (t, 1H), 3.02 (m, 1H), 1.28 (d, 6H).

MS: 457 (M+1)⁺

Example 43{4-[4-(4-Isopropyl-phenyl)-2-oxo-6-prop-2-ynyloxy-2H-quinazolin-1-ylmethyl]-phenoxy}-aceticacid

¹H NMR (400 MHz, DMSO-d6): 7.69 (d, 2H), 7.45-7.52 (m, 4H), 7.32 (d,1H), 7.20 (d, 2H), 6.79 (d, 2H), 5.40 (broad s, 2H), 4.77 (d, 2H), 4.33(s, 2H), 3.65 (t, 1H), 3.01 (m, 1H), 1.28 (d, 6H).

MS: 483 (M+1)⁺

Example 444-(4-Isopropyl-phenyl)-1-(4-methoxy-2,3-dimethyl-benzyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 7.74 (d, 2H), 7.49 (d, 2H), 7.44 (dd, 1H),7.38 (d, 1H), 7.21 (d, 1H), 6.63 (d, 1H), 6.32 (d, 1H), 5.37 (broad s,2H), 4.79 (d, 2H), 3.69 (t, 1H), 3.67 (s, 3H), 3.03 (m, 1H), 2.32 (s,3H), 2.15 (s, 3H), 1.29 (d, 6H).

MS: 467 (M+1)⁺

Example 451-(4-Benzyloxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 7.71 (d, 2H), 7.47-7.53 (m, 4H), 7.24-7.53(m, 8H), 6.97 (d, 2H), 5.43 (broad s, 2H), 5.05 (s, 2H), 4.78 (d, 2H),3.67 (t, 1H), 3.02 (m, 1H), 1.28 (d, 6H).

MS: 515 (M+1)⁺

Example 461-(3-Hydroxy-6-methyl-pyridin-2-ylmethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (400 MHz, DMSO-d6): 10.06 (s, 1H), 7.71 (d, 2H), 7.44-7.49 (m,4H), 7.35 (d, 1H), 7.12 (d, 1H), 6.96 (d, 1H), 5.46 (broad s, 2H), 4.79(d, 2H), 3.67 (t, 1H), 3.02 (m, 1H), 2.14 (s, 3H), 1.28 (d, 6H).

MS: 440 (M+1)⁺

Example 47{2-[4-(4-Isopropyl-phenyl)-2-oxo-6-prop-2-ynyloxy-2H-quinazolin-1-ylmethyl]-6-methoxy-phenoxy}-aceticacid

¹H NMR (400 MHz, DMSO-d6): 7.71 (d, 2H), 7.62 (d, 1H), 7.48 (d, 2H),7.43 (dd, 1H), 7.33 (d, 1H), 6.92 (dd, 1H), 6.84 (t, 1H), 6.22 (d, 1H),5.68 (broad s, 2H), 4.78 (d, 2H), 4.68 (s, 2H), 3.81 (s, 3H), 3.66 (t,1H), 3.02 (m, 1H), 1.28 (d, 6H).

MS: 513 (M+1)⁺

Example 484-(4-Isopropyl-phenyl)-1-(3-methoxy-benzyl)-6-propargyloxy-1H-quinazolin-2-one

¹H-NMR (300 MHz, CDCl₃): 7.75 (d, 2H), 7.49 (d, 1H), 7.39 (d, 2H),7.20-7.34 (m, 3H), 6.76-6.92 (m, 3H), 5.53 (broad, 2H), 4.64 (d, 2H),3.77 (s, 3H), 3.02 (hept, 1H), 2.55 (t, 1H), 1.33 (d, 6H).

MS: 439 (M+1)⁺

Example 494-(4-Isopropyl-phenyl)-1-(3,4-dimethoxy-benzyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 97° C.

¹H-NMR (300 MHz, CDCl₃): 7.75 (d, 2H), 7.49 (dd, 1H), 7.38 (d, 2H),7.32-7.36 (m, 2H), 6.96 (d, 1H), 6.87 (dd, 1H), 6.79 (d, 1H), 5.48(broad, 2H), 4.64 (d, 2H), 3.85 (s, 3H), 3.84 (s, 3H), 3.02 (hept, 1H),2.65 (t, 1H), 1.32 (d, 6H).

MS: 469 (M+1)⁺

Example 504-(4-Isopropyl-phenyl)-1-(4-methoxy-benzyl)-6-propargyloxy-1H-quinazolin-2-one

¹H-NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.48 (broad s, 1H), 7.38 (d, 2H),7.24-7.34 (m, 4H), 6.85 (d, 2H), 5.49 (broad, 2H), 4.64 (d, 2H), 3.77(s, 3H), 3.02 (hept, 1H), 2.55 (t, 1H), 1.32 (d, 6H).

MS: 439 (M+1)⁺

Example 514-(4-Isopropyl-phenyl)-1-(3,5-dimethoxy-benzyl)-6-propargyloxy-1H-quinazolin-2-one

¹H-NMR (300 MHz, CDCl₃): 7.75 (d, 2H), 7.48 (d, 1H), 7.38 (d, 2H), 7.31(d, 1H), 7.29 (s, 1H), 6.46 (d, 2H), 6.35 (t, 1H), 5.48 (broad, 2H),4.65 (d, 2H), 3.75 (s, 6H), 3.02 (hept, 1H), 2.55 (t, 1H), 1.33 (d, 6H).

MS: 469 (M+1)⁺

Example 524-(4-Isopropyl-phenyl)-1-(3,5-dimethoxy-benzyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 77-78° C.

¹H-NMR (300 MHz, CDCl₃): 7.76 (d, 2H), 7.47 (d, 1H), 7.38 (d, 2H),7.28-7.32 (m, 2H), 6.83 (d, 1H), 6.72 (dd, 1H), 6.65 (d, 1H), 5.54(broad, 2H), 4.64 (d, 2H), 4.12 (q, 2H), 3.85 (q, 2H), 3.02 (hept, 1H),2.54 (t, 1H), 1.49 (t, 3H), 1.33 (d, 6H), 1.28 (t, 3H).

MS: 497 (M+1)⁺

Example 534-(4-Isopropyl-phenyl)-1-(4-ethoxy-2-hydroxy-benzyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 186-187° C.

¹H-NMR (300 MHz, CDCl₃): 10.13 (broad, OH), 7.88 (d, 1H), 7.71 (d, 2H),7.54 (s, 1H), 7.52 (d, 1H), 7.34-7.40 (m, 3H), 6.51 (d, 1H), 6.42 (dd,1H), 5.41 (broad, 2H), 4.68 (d, 2H), 3.98 (q, 2H), 3.01 (hept, 1H), 2.56(t, 1H), 1.38 (t, 3H), 1.32 (d, 6H).

MS: 469 (M+1)⁺

Example 544-(4-Isopropyl-phenyl)-1-(2,4-diethoxy-benzyl)-6-propargyloxy-1H-quinazolin-2-one

¹H-NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.46 (d, 1H), 7.38 (d, 1H), 7.37(d, 2H), 7.29 (dd, 1H), 7.00 (d, 1H), 6.47 (d, 1H), 6.34 (dd, 1H), 5.49(broad, 2H), 4.64 (d, 2H), 4.13 (q, 2H), 3.96 (q, 2H), 3.01 (hept, 1H),2.54 (t, 1H), 1.51 (t, 3H), 1.38 (t, 3H), 1.32 (d, 6H).

MS: 497(M+1)⁺

Example 554-(4-Isopropyl-phenyl)-1-(2,4-diethoxy-benzyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 199-201° C.

¹H-NMR (300 MHz, CDCl₃): 9.15 (broad, OH), 7.85 (d, H), 7.71 (d, 2H),7.49-7.56 (m, 3H), 7.38 (d, 2H), 7.01 (d, 1H), 6.90 (d, 1H), 6.79 (dd,1H), 5.44 (broad, 2H), 4.68 (d, 2H), 3.97 (q, 2H), 3.02 (hept, 1H), 2.57(t, 1H), 1.39 (t, 3H), 1.32 (d, 6H).

MS: 469 (M+1)⁺

Example 564-(4-Isopropyl-phenyl)-1-(2-methoxy-benzyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.76 (d, 2H), 7.48 (d, 1H), 7.38 (d, 2H),7.18-7.32 (m, 3H), 6.76-7.02 (m, 3H), 5.56 (s, 2H), 4.62 (d, 2H), 3.96(s, 3H), 3.02 (hept, 1H), 2.56 (t, 1H), 1.32 (d, 6H).

MS: 439 (M+1)⁺

Example 574-(4-Isopropyl-phenyl)-1-(4-ethoxy-benzyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 181-183° C.

¹H-NMR (300 MHz, CDCl₃): 7.73 (d, 2H), 7.47 (s, 1H), 7.37 (d, 2H), 7.30(s, 2H), 7.22-7.28 (m, 2H), 6.83 (d, 2H), 5.47 (broad, 2H), 4.63 (d,2H), 3.98 (q, 2H), 3.01 (hept, 1H), 2.53 (broad, 1H), 1.38 (t, 3H), 1.31(d, 6H).

MS: 453 (M+1)⁺

Example 584-(4-Isopropyl-phenyl)-1-(3-isopropoxy-benzyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 69° C.

¹H-NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.48 (d, 1H), 7.37 (d, 2H), 7.28(td, 1H), 7.25 (d, 1H), 7.19 (d, 1H), 6.74-6.88 (m, 3H), 5.50 (broad,2H), 4.63 (d, 2H), 4.50 (hept, 1H), 3.01 (hept, 1H), 2.54 (t, 1H), 1.32(d, 6H), 1.29 (d, 6H).

MS: 467 (M+1)⁺

Example 594-(4-Isopropyl-phenyl)-1-(2,4-diethoxy-benzyl)-6-propargyloxy-1H-quinazolin-2-one

¹H-NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.48 (d, 1H), 7.37 (d, 2H),7.26-7.33 (m, 2H), 7.20 (d, 1H), 6.83-6.90 (m, 2H), 6.75-6.80 (m, 1H),5.51 (broad, 2H), 4.63 (d, 2H), 3.87 (t, 2H), 3.01 (hept, 1H), 2.54 (t,1H), 1.76 (hex, 2H), 1.32 (d, 6H), 1.00 (t, 3H).

MS: 467 (M+1)⁺

Example 601-(4-Bromo-3-methoxy-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 72-74° C.

¹H-NMR (300 MHz, CDCl₃): 7.76 (d, 2H), 7.48-7.54 (m, 2H), 7.38 (d, 2H),7.32 (dd, 1H), 7.04 (d, 1H), 6.68 (dd, 1H), 6.47 (d, 1H), 5.53 (broad s,2H), 4.65 (d, 2H), 3.64 (s, 3H), 3.02 (hept, 1H), 2.55 (t, 1H), 1.32 (d,6H).

MS: 517/519 (M+1)⁺

Example 614-(4-Isopropyl-phenyl)-1-(3-hydroxy-4-methoxy-benzyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 112° C.

¹H-NMR (300 MHz, CDCl₃): 7.73 (d, 2H), 7.47 (d, 1H), 7.37 (d, 2H),7.25-7.33 (m, 2H), 6.88 (d, 1H), 6.82 (dd, 1H), 6.77 (d, 1H), 5.60 (s,OH), 5.45 (broad s, 2H), 4.63 (d, 2H), 3.85 (s, 3H), 3.01 (hept, 1H),2.54 (t, 1H), 1.32 (d, 6H).

MS: 455 (M+1)⁺

Example 624-(4-Isopropyl-phenyl)-1-(2-methoxymethoxy-benzyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.76 (d, 2H), 7.48 (d, 1H), 7.38 (d, 2H),7.10-7.32 (m, 4H), 7.02 (d, 1H), 6.86 (t, 1H), 5.58 (s, 2H), 5.34 (s,2H), 4.62 (d, 2H), 3.58 (s, 3H), 3.02 (hept, 1H), 2.56 (t, 1H), 1.32 (d,6H).

MS: 469 (M+1)⁺

Example 631-(4-Bromo-3-ethoxy-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 144-146° C.

¹H-NMR (300 MHz, CDCl₃): 7.77 (d, 2H), 7.50 (s, 1H), 7.49 (d, 1H), 7.39(d, 2H), 7.32 (dd, 1H), 7.04 (d, 1H), 6.67 (dd, 1H), 6.48 (d, 1H), 5.53(broad s, 2H), 4.65 (d, 2H), 3.84 (q, 2H), 3.02 (hept, 1H), 2.55 (t,1H), 1.32 (d, 6H), 1.28 (t, 3H).

MS: 532 (M+1)⁺

Example 641-(4-Chloro-4-methoxy-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 159-161° C.

¹H-NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.48 (d, 1H), 7.30-7.40 (m, 4H),7.17-7.28 (m, 2H), 6.86 (d, 1H), 5.45 (broad s, 2H), 4.64 (d, 2H), 3.86(s, 3H), 3.01 (hept, 1H), 2.54 (t, 1H), 1.31 (d, 6H).

MS: 487 (M+1)⁺

Example 651-(3-Chloro-4-methoxy-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 147-149° C.

¹H-NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.49 (d, 1H), 7.39 (s, 1H), 7.37(d, 2H), 7.30-7.36 (m, 2H), 7.22-7.26 (m, 1H), 7.17 (dd, 1H), 6.85 (d,1H), 5.44 (broad s, 2H), 4.64 (d, 2H), 4.07 (q, 2H), 3.01 (hept, 1H),2.55 (t, 1H), 1.44 (t, 3H), 1.32 (d, 6H).

MS: 473 (M+1)⁺

Example 661-(3-Chloro-4,5-dimethoxy-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 80° C.

¹H-NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.51 (d, 1H), 7.33-7.41 (m, 3H),7.28 (s, 1H), 6.88 (dd, 2H), 5.43 (broad s, 2H), 4.65 (d, 2H), 3.82 (s,3H), 3.81 (s, 3H), 3.01 (hept, 1H), 2.55 (t, 1H), 1.32 (d, 6H).

MS: 503, 505 (M+1)⁺

Example 671-(4-Chloro-3-methoxy-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 133-135° C.

¹H NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.50 (d, 1H), 7.33 (d, 2H),7.22-7.36 (m, 3H), 6.97 (d, 1H), 6.83 (dd, 1H), 5.49 (broad s, 2H), 4.64(d, 2H), 3.85 (s, 3H), 3.01 (hept, 1H), 2.54 (t, 1H), 1.32 (d, 6H).

MS: 473 (M+1)⁺

Example 681-(3-Fluoro-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 72-73° C.

¹H NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.50 (d, 1H), 7.37 (d, 2H), 7.30(td, 2H), 7.18 (d, 1H), 7.08 (d, 1H), 6.90-7.02 (m, 2H), 5.53 (broad s,2H), 4.63 (d, 2H), 3.01 (hept, 1H), 2.54 (t, 1H), 1.31 (d, 6H).

MS: 427 (M+1)⁺

Example 691-(3,4-Difluoro-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 84° C.

¹H NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.51 (d, 1H), 7.38 (d, 2H), 7.33(dd, 1H), 7.02-7.22 (m, 4H), 5.48 (broad s, 2H), 4.64 (d, 2H), 3.01(hept, 1H), 2.55 (t, 1H), 1.31 (d, 6H).

MS: 445 (M+1)⁺

Example 701-(4-Chloro-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.51 (d, 1H), 7.38 (d, 2H), 7.33(dd, 1H), 7.02-7.22 (m, 4H), 5.48 (broad s, 2H), 4.64 (d, 2H), 3.01(hept, 1H), 2.55 (t, 1H), 1.31 (d, 6H).

MS: 443, 445 (M+1)⁺

Example 711-(4-Fluoro-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 71-73° C.

¹H NMR (300 MHz, CDCl₃): 7.73 (d, 2H), 7.48 (d, 1H), 7.37 (d, 2H),7.20-7.34 (m, 4H), 7.00 (t, 2H), 5.50 (broad s, 2H), 4.63 (d, 2H), 3.01(hept, 1H), 2.54 (broad t, 1H), 1.31 (d, 6H).

MS: 427 (M+1)⁺

Example 721-(3-chloro-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 110-112° C.

¹H NMR (300 MHz, CDCl₃): 7.75 (d, 2H), 7.50 (d, 1H), 7.38 (d, 2H),7.21-7.35 (m, 4H), 7.18 (d, 2H), 5.51 (broad s, 2H), 4.64 (d, 2H), 3.01(hept, 1H), 2.54 (broad t, 1H), 1.32 (d, 6H).

MS: 443, 445 (M+1)⁺

Example 731-(3-Bromo-4-hydroxy-5-methoxy-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 175-177° C.

¹H NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.50 (d, 1H), 7.37 (d, 2H), 7.32(t, 2H), 7.07 (broad d, 1H), 6.89 (broad d, 1H), 5.42 (broad s, 2H),4.65 (d, 2H), 3.85 (s, 3H), 3.01 (hept, 1H), 2.55 (broad t, 1H), 1.31(d, 6H).

MS: 533, 535 (M+1)⁺

Example 741-(3-Bromo-4-hydroxy-5-methoxy-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 175-177° C.

¹H NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.50 (d, 1H), 7.37 (d, 2H), 7.32(t, 2H), 7.07 (broad d, 1H), 6.89 (broad d, 1H), 5.42 (broad s, 2H),4.65 (d, 2H), 3.85 (s, 3H), 3.01 (hept, 1H), 2.55 (broad t, 1H), 1.31(d, 6H).

MS: 533, 535 (M+1)⁺

Example 751-(4-Bromo-4-hydroxy-5-methoxy-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 122-123° C.

¹H NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.50 (d, 1H), 7.45 (d, 2H), 7.38(d, 2H), 7.32 (dd, 1H), 7.16-7.22 (m, 3H), 5.49 (broad s, 2H), 4.64 (d,2H), 3.02 (hept, 1H), 2.55 (broad t, 1H), 1.32 (d, 6H).

MS: 487, 489 (M+1)⁺

Example 761-(3-Bromo-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 144-146° C.

¹H NMR (300 MHz, CDCl₃): 7.75 (d, 2H), 7.51 (d, 1H), 7.46 (broad s, 1H),7.28-7.41 (m, 4H), 7.14-7.25 (m, 3H), 5.51 (broad s, 2H), 4.65 (d, 2H),3.02 (hept, 1H), 2.56 (broad t, 1H), 1.32 (d, 6H).

MS: 487, 489 (M+1)⁺

Example 771-(3-Bromo-4,5-dimethoxy-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 132-142° C.

¹H NMR (300 MHz, CDCl₃): 7.80 (d, 2H), 7.56 (d, 1H), 7.43 (d, 2H), 7.41(d, 1H), 7.32 (d, 1H), 7.12 (br d, 1H), 5.48 (broad s, 2H), 4.70 (d,2H), 3.86 (s, 6H), 3.06 (hept, 1H), 2.60 (broad t, 1H), 1.36 (d, 6H).

MS: 546, 548 (M+1)⁺

Example 781-(3,4-Dibromo-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 86-88° C.

¹H NMR (300 MHz, CDCl₃): 7.75 (d, 2H), 7.50-7.61 (m, 3H), 7.32-7.42 (m,3H), 7.10-7.19 (m, 2H), 5.46 (broad s, 2H), 4.66 (broad s, 2H), 3.02(hept, 1H), 2.55 (broad, 1H), 1.32 (d, 6H).

MS: 565, 567, 569 (M+1)⁺ (Br₂-isotope pattern)

Example 791-(3,4-Dichloro-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 73-74° C.

¹H NMR (300 MHz, CDCl₃): 7.75 (d, 2H), 7.52 (d, 1H), 7.31-7.44 (m, 5H),7.16 (d, 2H), 5.48 (broad s, 2H), 4.65 (broad d, 2H), 3.02 (hept, 1H),2.55 (broad, 1H), 1.32 (d, 6H).

MS: 477, 479, 481 (M+1)⁺ (Cl₂-isotope pattern)

Example 801-(4-Methyl-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 92-93° C.

¹H NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.47 (s, 1H), 7.37 (d, 2H), 7.29(s, 2H), 7.21 (d, 2H), 7.12 (d, 2H), 5.51 (broad s, 2H), 4.63 (broad d,2H), 3.01 (hept, 1H), 2.55 (broad, 1H), 2.31 (s, 3H), 1.32 (d, 6H).

MS: 423 (M+1)⁺

Example 811-(3-Methyl-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 115-116° C.

¹H NMR (300 MHz, CDCl₃): 7.75 (d, 2H), 7.48 (d, 1H), 7.38 (d, 2H),7.27-7.34 (m, 2H), 7.20 (t, 1H), 7.03-7.14 (m, 3H), 5.51 (broad s, 2H),4.64 (d, 2H), 3.02 (hept, 1H), 2.54 (broad, 1H), 2.31 (s, 3H), 1.32 (d,6H).

MS: 423 (M+1)⁺

Example 821-(4-Ethyl-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 75-76° C.

¹H NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.48 (s, 1H), 7.38 (d, 2H), 7.30(s, 2H), 7.23 (d, 2H), 7.14 (d, 2H), 5.52 (broad s, 2H), 4.63 (d, 2H),3.02 (hept, 1H), 2.61 (q, 2H), 2.54 (broad t, 1H), 1.32 (d, 6H), 1.20(t, 3H).

MS: 437 (M+1)⁺

Example 831-(3,4-Dimethyl-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 143-144° C.

¹H NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.47 (s, 1H), 7.38 (d, 2H), 7.31(broad d, 2H), 7.02-7.12 (m, 3H), 5.48 (broad s, 2H), 4.63 (d, 2H), 3.01(hept, 1H), 2.54 (broad t, 1H), 2.21 (s, 6H), 1.32 (d, 6H).

MS: 437 (M+1)⁺

Example 841-Cyclopropylmethyl-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

¹H-NMR (300 MHz, CDCl₃): 7.70 (d, 2H), 7.43-7.50 (m, 3H), 7.38 (d, 2H),7.35 (d, 2H), 4.67 (d, 2H), 4.26 (d, 2H), 3.00 (hept, 1H), 2.55 (t, 1H),1.30 (d, 6H), 0.52-0.67 (m, 4H).

MS: 373 (M+1)⁺

Example 851-(2-Bromo-thiazol-5-ylmethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H-NMR (300 MHz, CDCl₃): 7.66-7.72 (m, 3H), 7.32-7.52 (m, 5H), 5.54 (s,2H), 4.66 (d, 2H), 2.98 (hept, 1H), 2.54 (t, 1H), 1.32 (d, 6H).

MS: 496 (M+1)⁺

Example 861-(4,5-Dichloro-thiophen-2-ylmethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H-NMR (300 MHz, CDCl₃): 7.76 (d, 2H), 7.36-7.54 (m, 5H), 6.96 (s, 1H),5.48 (s, 2H), 4.62 (d, 2H), 3.02 (hept, 1H), 2.58 (t, 1H), 1.32 (d, 6H).

MS: 483 (M+1)⁺

Example 874-(4-Isopropyl-phenyl)-1-(5-methyl-thiophen-2-ylmethyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H-NMR (300 MHz, CDCl₃): 7.72 (d, 2H), 7.30-7.60 (m, 5H), 6.96 (d, 1H),6.58 (d, 1H), 5.54 (s, 2H), 4.64 (d, 2H), 3.02 (hept, 1H), 2.54 (t, 1H),2.42 (s, 3H), 1.30 (d, 6H).

MS: 429 (M+1)⁺

Example 884-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-1-quinolin-2-ylmethyl-1H-quinazolin-2-one

¹H-NMR (300 MHz, CDCl₃): 8.16 (d, 2H), 7.62-7.82 (m, 5H), 7.56 (d, 2H),7.26-52 (d, 4H), 5.92 (s, 2H), 4.62 (d, 2H), 3.02 (hept, 1H), 2.52 (t,1H), 1.32 (d, 6H).

MS: 460 (M+1)⁺

Example 894-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-1-[2-(2,6,6-trimethyl-cyclohex-1-enyl)-ethyl]-1H-quinazolin-2-one

¹H-NMR (300 MHz, CDCl₃): 7.72 (d, 2H), 7.42-7.50 (m, 3H), 7.42 (d, 2H),4.68 (d, 2H), 4.26 (t, 2H), 3.02 (hept, 1H), 2.56 (t, 1H), 2.50 (t, 2H),1.98 (t, 2H), 1.93 (s, 3H), 1.62 (d, 2H), 1.48 (d, 2H), 1.32 (d, 6H),1.16 (s, 3H).

MS: 469 (M+1)⁺

Example 904-Ethyl-4-{[2-(4-isopropyl-benzoyl)-4-prop-2-ynyloxy-phenylamino]-methyl}-hexanoicacid

¹H-NMR (300 MHz, CDCl₃): 7.62 (d, 2H), 7.36-7.82 (m, 5H), 4.58 (d, 2H),2.84-3.08 (m, 3H), 2.48 (t, 1H), 2.32 (m, 2H), 1.74 (m, 2H), 1.42 (m,4H), 1.32 (d, 6H), 0.82 (m, 6H).

MS: 450 (M+1)⁺

Example 914-(4-Isopropyl-phenyl)-6-propargyloxy-1-(3,3,3-trifluoro-propyl)-1H-quinazolin-2-one

¹H-NMR (300 MHz, CDCl₃): 7.69 (d, 2H), 7.51 (s, 1H), 7.49 (dd, 1H), 7.37(d, 2H), 7.33 (d, 1H), 4.68 (d, 2H), 4.47-4.56 (m, 2H), 3.01 (hept, 1H),2.60-2.78 (m, 2H), 2.57 (t, 1H), 1.31 (d, 6H).

MS: 415 (M+1)⁺

Example 921-(3,3-Dimethyl-butyl)-4-(4-Isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

¹H-NMR (300 MHz, CDCl₃): 7.68 (d, 2H), 7.42-7.48 (m, 2H), 7.35 (d, 2H),7.32 (d, 1H), 4.66 (d, 2H), 4.25-4.35 (m, 2H), 3.00 (hept, 1H), 2.56 (t,1H), 1.66-1.74 (m, 2H), 1.31 (d, 6H), 1.10 (s, 9H). m.p. 69° C.

MS: 403 (M+1)⁺

Example 931-(2,2-Dimethyl-pent-4-enyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.78 (d, 2H), 7.36-7.52 (m, 5H), 5.90 (m, 1H),5.12 (m, 2H), 4.68 (d, 2H), 4.32 (broad s, 2H), 3.02 (hept, 1H), 2.58(m, 1H), 2.18 (d, 2H), 1.32 (d, 6H), 1.02 (s, 6H).

MS: 415 (M+1)⁺

Example 941-(3,5-Dimethyl-1-phenyl-1H-pyrazol-4-ylmethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.78 (d, 2H), 7.52 (d, 1H), 7.26-7.50 (m, 9H),5.48 (s, 2H), 4.66 (d, 2H), 3.02 (hept, 1H), 2.56 (m, 1H), 2.32 (s, 3H),2.22 (s, 3H), 1.32 (d, 6H).

MS: 503 (M+1)⁺

Example 951-(5-Bromo-thiophen-2-ylmethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.68 (d, 2H), 7.31-7.50 (m, 5H), 7.34 (d, 2H),6.94 (d, 1H), 6.88 (d, 1H), 5.52 (s, 2H), 4.64 (d, 2H), 3.00 (hept, 1H),2.56 (m, 1H), 1.30 (d, 6H).

MS: 495 (M+1)⁺

Example 961-(5-Hydroxymethyl-furan-2-ylmethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.70 (d, 2H), 7.62 (d, 1H), 7.42-7.52 (m, 2H),7.38 (d 2H), 6.38 (d, 1H), 6.22 (d, 1H), 6.96 (dd, 1H), 5.48 (s, 2H),4.52-4.70 (m, 4H), 3.02 (hept, 1H), 2.58 (t, 1H), 1.32 (d, 6H).

MS: 429 (M+1)⁺

Example 971-(2-Butyl-5-chloro-1H-imidazol-4-ylmethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.72 (d, 1H), 7.46-7.60 (m, 3H), 7.38 (d, 2H),5.36 (s, 2H), 4.66 (d, 2H), 3.00 (hept, 1H), 2.70 (m, 2H), 2.56 (t, 1H),1.66 (m, 2H), 1.30 (d, 6H), 0.86 (t, 3H).

MS: 489 (M+1)⁺

Example 984-(4-Isopropyl-phenyl)-1-(6-methoxy-pyridin-3-ylmethyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 8.22 (m, 1H), 7.64-7.78 (m, 3H), 7.50 (d, 1H),7.30-7.42 (m, 4H), 6.72 (d, 1H), 5.48 (s, 2H), 4.66 (d, 2H), 3.94 (s,3H), 3.02 (hept, 1H), 2.56 (t 1H), 1.32 (d, 6H).

MS: 440 (M+)⁺

Example 997-[4-(4-Isopropyl-phenyl)-2-oxo-6-prop-2-ynyloxy-2H-quinazolin-1-ylmethyl]-1H-indole-2-carbonitrile

¹H NMR (300 MHz, CDCl₃): 11.52 (s, 1H), 7.92 (d, 1H), 7.74 (d, 2H), 7.64(t, 2H), 7.46-7.54 (m, 2H), 7.38 (d, 2H), 7.12-7.26 (m, 2H), 6.76 (broads, 2H), 4.64 (d, 2H), 3.02 (hept, 1H), 2.56 (t 1H), 1.32 (d, 6H).

MS: 473 (M+1)⁺

Example 1001-(2,4-Diamino-pyrimidin-5-ylmethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (300 MHz, CD₃OD): 7.40-7.80 (m, 8H), 5.36 (s, 2H), 4.74 (d, 2H),2.98-3.12 (m, 2H), 1.32 (d, 6H).

MS: 441 (M+1)⁺

Example 1011-(6-Hydroxymethyl-pyridin-2-ylmethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.76 (d, 2H), 7.64 (t, 1H), 7.20-7.52 (m, 6H),7.16 (d, 1H), 5.64 (s, 2H), 4.76 (s, 2H), 4.64 (d, 2H), 3.02 (hept, 1H),2.56 (t, 1H), 1.32 (d, 6H).

MS: 440 (M+1)

Example 1021-(3,5-Di-tert-butyl-4-hydroxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.76 (d, 2H), 7.30-7.52 (m, 5H), 7.16 (s, 2H),5.44 (s, 2H), 4.66 (s, 2H), 3.02 (hept, 1H), 2.56 (t, 1H), 1.30 (d, 6H).

MS: 537 (M+1)⁺

Example 1034-[4-(4-Isopropyl-phenyl)-2-oxo-6-prop-2-ynyloxy-2H-quinazolin-1-ylmethyl]-2,2-dimethyl-oxazolidine-3-carboxylicacid tert-butyl ester

¹H NMR (300 MHz, CDCl₃): 8.20 (d, 1H), 7.70 (d, 2H), 7.30-7.58 (m, 4H),4.94 (dd, 1H), 4.66 (d, 2H), 4.31 (d, 2H), 4.20 (m, 1H), 3.84 (dd, 1H),3.00 (hept, 1H), 2.56 (t, 1H), 1.40-1.64 (m, 15H), 1.32 (d, 6H).

MS: 532 (M+1)⁺

Example 1044-(4-Isopropyl-phenyl)-1-(4-methylamino-2-methylsulphanyl-pyrimidin-5-ylmethyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 8.18 (s, 1H), 7.86 (d, 1H), 7.72 (d, 2H), 7.64(d, 1H), 7.52 (d, 1H), 7.44 (dd, 1H), 7.38 (d, 2H), 5.34 (broad s, 2H),4.64 (d, 2H), 3.02 (hept, 1H), 2.96 (d, 3H), 2.58 (t, 1H), 2.50 (s, 3H),1.32 (d, 6H).

MS: 486 (M+1)⁺

Example 1054-(4-Isopropyl-phenyl)-1-{4-[2-(methyl-pyridin-2-yl-amino)-ethoxy]-benzyl}-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 8.12 (dd, 1H), 7.74 (d, 2H), 7.20-7.50 (m, 7H),6.84 (d, 2H), 6.46-6.56 (m, 2H), 5.46 (broad s, 2H), 4.64 (d, 2H), 4.36(t, 2H), 3.92 (t, 2H), 3.12 (s, 3H), 3.02 (hept, 1H), 2.54 (t, 1H),1.40-1.64 (m, 15H), 1.32 (d, 6H).

MS: 559 (M+1)⁺

Example 1064-(4-Isopropyl-phenyl)-1-(2-methyl-hex-4-enyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.72 (d, 2H), 7.30-7.52 (m, 5H), 5.42 (m, 2H),4.64 (d, 2H), 4.24 (m, 2H), 3.00 (hept, 1H), 2.58 (t, 1H), 2.00-2.22 (m,3H), 1.62 (d, 3H), 1.30 (d, 6H), 0.98 (d, 3H).

MS: 415 (M+1)⁺

Example 1074-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-1-(4-pyrazin-2-yl-benzyl)-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 8.88 (s, 1H), 8.60 (d, 1H), 8.46 (d, 1H), 7.88(d, 2H), 7.76 (d, 2H), 7.20-7.58 (m, 6H), 5.62 (broad s, 2H), 4.64 (d,2H), 3.02 (hept, 1H), 2.56 (t, 1H), 1.32 (d, 6H).

MS: 487 (M+1)⁺

Example 1084-(4-Isopropyl-phenyl)-1-(3-methylsulphanyl-propyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.72 (d, 2H), 7.48-7.52 (m, 3H), 7.38 (d, 2H),4.69 (d, 2H), 4.43 (dd, 2H), 3.58 (t, 2H), 3.03 (hept, 1H), 2.71 (m,2H), 2.58 (m, 1H), 2.08-2.32 (m, 5H), 1.31 (d, 6H).

MS: 407 (M+1)⁺

Example 1094-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-1-thiophen-2-ylmethyl-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.72 (d, 2H), 7.39-7.51 (m, 3H), 7.38 (d, 2H),7.21 (dd, 1H), 7.18 (dd, 1H), 6.96 (dd, 1H), 5.65 (s, 2H), 4.66 (d, 2H),3.00 (hept, 1H), 2.58 (t, 1H), 1.31 (d, 6H).

MS: 415 (M+1)⁺

Example 1101-Benzyl-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline-2-thione

To a solution of 140 mg (0.365 mmol)(2-benzylamino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone in5 ml acetic acid is added 68 mg (0.695 mmol) potassium thiocyanate. Thereaction is stirred for two days at 60° C. The solvent is removed andthe residue is extracted with water/dichloromethane. After evaporationof the organic phase the crude product is purified byflash-chromatography (MeOH/CH₂Cl₂, 1:9) to give 25 mg (16%) of a yellowoil.

¹H NMR (300 MHz, CDCl₃): 7.82 (d, 2H), 7.52 (s, 1H), 7.20-7.43 (m, 9H),6.22 (broad s, 2H), 4.64 (d, 2H), 3.02 (hept, 1H), 2.56 (t, 1H), 1.32(d, 6H).

MS: 425 (M+1)⁺

Example 1114-(4-Isopropyl-phenyl)-1-(3-methane-sulphonyl-benzyl)-6-propargyloxy-1H-quinazoline-2-thione

A solution of 1.87 g (4.06 mmol)4-(4-isopropyl-phenyl)-1-(3-methane-sulphonyl-benzyl)-5-propargyloxy-phenyl-methanone(example 2) and 0.72 g (4.42 mmol) benzoylisothiocyanate in 9 ml THF isstirred at 50° C. for 2 h. Then the reaction mixture is cooled to roomtemperature and K₂CO₃ (1.2 g suspended in 17 ml MeOH) is added andstirring is continued for 20 h. After that the reaction mixture ispoured onto water and extracted with ethyl acetate. The combined organiclayers are washed with water and brine, dried over MgSO₄, filtered andconcentrated in vacuo. The residue is purified by flash-chromatographyon silica gel (hexane/EtOAc=1:1) to afford the title compound as a darkyellow foam.

¹H-NMR (300 MHz, DMSO-d₆): 7.88 (s, 1H), 7.78 (d, 1H), 7.75 (d, 2H),7.58-7.38 (m, 7H), 4.80 (s, 2H), 3.48 (m, 1H), 3.18 (s, 3H), 2.99 (m,1H), 1.22 (d, 6H).

MS: 503 (M+1)⁺

The compounds of the following examples are prepared by analogy:

Example 1124-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-1-thiophen-2-ylmethyl-1Hquinazoline-2-thione

¹H NMR (300 MHz, CDCl₃): 7.76 (d, 2H), 7.64 (d, 1H), 7.50 (d, 1H), 7.44(dd, 1H), 7.38 (d, 2H), 7.12-7.30 (m, 2H), 6.88 (m, 1H), 6.32 (broad s,2H), 4.68 (d, 2H), 3.02 (hept, 1H), 2.58 (t, 1H), 1.32 (d, 6H).

MS: 431 (M+1)⁺

Example 1131-[3-(2-Hydroxy-ethoxy)-benzyl]-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline-2-thione

¹H-NMR (300 MHz, CDCl₃): 7.82 (d, 2H), 7.52 (m, 1H), 7.20-7.42 (m, 5H),6.76-6.94 (m, 3H), 6.18 (broad s, 2H), 4.66 (d, 2H), 4.03 (t, 2H), 3.92(t, 2H), 3.00 (hept, 1H), 2.56 (t, 1H), 1.30 (d, 6H).

MS: 485 (M+1)⁺

Example 1141-Benzyl-4-(4-isopropyl-phenyl)-6-methoxy-1H-quinazoline-2-thione

¹H NMR (300 MHz, CDCl₃): 7.76 (d, 2H), 7.39-7.23 (m, 10H), 6.21 (s,broad, 1H), 3.76 (s, 3H), 3.00 (hept, 1H), 1.30 (d, 6H).

MS: 401 (M+1)⁺

Example 1154-(4-Isopropyl-phenyl)-1-[2-(2-methoxy-ethoxy)-pyridin-3-ylmethyl]-6-propargyloxy-1H-quinazolin-2-thione

¹H-NMR (300 MHz, CDCl₃): 7.76 (d, 2H), 7.44-7.55 (m, 3H), 7.32-7.38 (m,3H), 6.91 (d, 1H), 6.68 (d, 1H), 4.66 (d, 2H), 4.35-4.40 (m, 2H),3.64-3.69 (m, 2H), 3.40 (s, 3H), 2.99 (hept, 1H), 2.55 (t, 1H), 1.30 (d,6H).

MS: 500 (M+1)⁺

Example 1164-(4-Isopropyl-phenyl)-1-[2-(2-methoxy-ethoxy)-pyridin-3-ylmethyl]-6-propargyloxy-1H-quinazolin-2-thione

m.p. 174-175° C.

¹H-NMR (300 MHz, CDCl₃): 7.72 (d, 2H), 7.42-7.52 (m, 3H), 7.33 (d, 2H),4.69 (d, 2H), 2.99 (hept, 1H), 2.57 (t, 1H), 1.85 (very broad, 2H), 1.29(d, 6H), 1.12 (s, 9H).

MS: 419 (M+1)⁺

Example 1171-Benzo[1,2,5]thiadiazol-5-ylmethyl-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-thione

m.p. 102-106° C.

¹H-NMR (300 MHz, CDCl₃): 8.02 (d, 1H), 7.81 (d, 2H), 7.70 (broad s, 1H),7.63 (dd, 1H), 7.55 (d, 1H), 7.39 (d, 2H), 7.26-7.35 (m, 2H), 4.66 (d,2H), 3.02 (hept, 1H), 2.55 (t, 1H), 1.32 (d, 6H).

MS: 483 (M+1)⁺

Example 118 Acetic acid2-{3-[4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-2-thioxo-2H-quinazolin-1-ylmethyl]-phenoxy}-ethylester

¹H-NMR (300 MHz, CDCl₃): 7.79 (d, 2H), 7.52 (m, 1H), 7.21-7.41 (m, 5H),6.76-6.93 (m, 3H), 6.18 (bs, 2H), 4.66 (d, 2H), 4.37 (t, 2H), 4.12 (t,2H), 3.04 (hept, 1H), 2.58 (t, 1H), 2.08 (s, 3H), 1.32 (d, 6H).

MS: 527 (M+1)⁺

Example 1191-(2,3-Dimethoxy-quinoxalin-6-ylmethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline

¹H-NMR (300 MHz, CDCl₃): 7.80 (d, 2H), 7.70 (d, 1H), 7.52 (d, 1H),7.16-7.40 (m, 6H), 6.76 (bs, 2H), 4.64 (d, 2H), 4.22 (s, 3H), 4.18 (s,3H), 3.00 (hept, 1H), 2.52 (t, 1H), 1.30 (d, 6H).

MS: 537 (M+1)⁺

Example 1201-[3-(2-Hydroxy-ethoxy)-thiophen-2-ylmethyl]-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline-2-thione

¹H-NMR (300 MHz, CDCl₃): 8.02 (d, 1H), 7.76 (d, 2H), 7.42-7.52 (m, 3H),7.38 (d, 2H), 7.16 (d, 1H), 6.80 (d, 1H), 6.22 (bs, 2H), 4.64 (d, 2H),4.28 (t, 2H), 4.08 (m, 2H), 3.00 (hept, 1H), 2.56 (t, 1H), 1.30 (d, 6H).

MS: 491 (M+1)⁺

Example 1211-Isopropyl-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline-2-thione

A suspension of 50 mg (0.139 mmol)1-isopropyl-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline-2-oneand 56 mg (0.139 mmol) Lawesson's reagent in 2 ml benzene is heated to70° C. overnight. The reaction mixture is extracted(water/di-chloromethane) and the organic layer is dried and evaporated.

Flash-chromatography (hexanes/ethyl acetate) yields the product as anorange oil.

¹H-NMR (300 MHz, CDCl₃): 7.78 (d, 2H), 7.46 (d, 1H), 7.42 (dd, 1H), 7.36(d, 2H), 6.52 (hept, 1H), 4.72 (d, 2H), 3.02 (hept, 1H), 2.58 (t, 1H),1.78 (d, 6H), 1.30 (d, 6H).

MS: 377 (M+1)⁺

Example 1221-Benzyl-4-(4-cyclopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

A. Synthesis of 1-bromo-4-cyclopropyl-benzene

A solution of 5.0 g (42.3 mmol) cyclopropyl benzene and 300 mg of thecatalyst iron(III) bromide in 30 ml carbon tetrachloride is cooled to 0°C. and treated dropwise with 6.76 g (42.3 mmol) bromine (diluted with anequal volume of CCl₄). The bromination is complete after ½ h. Extractiveworkup with dichloromethane and aqueous sodium thiosulphate solutionaffords a yellow oil, which is purified by flash chromatography(petroleum ether to yield a slightly yellow liquid.

¹H-NMR (300 MHz, CDCl₃): 7.35 (d, 2H), 6.93 (d, 2H), 1.80-1.90 (m, 1H),0.94-1.01 (m, 2H), 0.63-0.70 (m, 2H).

B. Synthesis of(2-nitro-5-propargyloxyphenyl)-(4-cyclopropyl-phenyl)-methanol

A suspension of 407 mg (16.7 mmol) magnesium turnings in 5 ml anhydrousTHF is treated with a solution of 1-bromo-4-cyclopropyl-benzene in 20 mlTHF at such a rate to maintain gentle reflux. Stirring is continued foranother ½ h after complete addition. The resulting Grignard reagent isthen slowly added to a solution of 2-nitro-5-propargyloxy-benzaldehydein 30 ml THF at −75° C. The reaction is kept between −75° C. and −65° C.throughout the addition, followed by slow warming to rt. The mixture isthen poured into saturated aqueous ammonium chloride solution andextracted with diethyl ether. Purification of the crude product by flashchromatography (hexane/dichloromethane) yields a yellow brown oil.

¹H-NMR (300 MHz, CDCl₃): 8.06 (d, 1H), 7.41 (d, 1H), 7.21 (d, 2H), 7.01(d, 2H), 6.97 (dd, 1H), 6.49 (d, 1H), 4.78 (d, 1H), 2.68 (d, OH), 2.55(t, 1H), 1.82-1-92 (m, 1H), 0.91-0.99 (m, 2H), 0.64-0.70 (m, 2H).

C. Synthesis of(2-nitro-5-propargyloxyphenyl)-(4-cyclopropyl-phenyl)-methanone

A solution of 2.8 g (8.66 mmol) of the alcohol prepared in step B in 20ml acetone is treated dropwise with 4.3 ml 2.6 M Jones reagent. Anexothermic reaction occurs and the mixture turns dark. After 2 h thechromium salts formed are separated and rinsed several times withdichloromethane. The combined organic phases are concentrated and thecrude product obtained is purified by chromatography(hexane/dichloromethane) to yield white crystals.

m.p. 107° C.

¹H-NMR (300 MHz, CDCl₃): 8.24 (d, 1H), 7.64 (d, 2H), 7.16 (dd, 1H), 7.09(d, 2H), 6.95 (d, 1H), 4.80 (d, 1H), 2.58 (t, 1H), 1.89-1-99 (m, 1H),1.03-1.12 (m, 2H), 0.75-0.83 (m, 2H).

MS: 322 (M+1)⁺

D. Synthesis of(2-amino-5-propargyloxyphenyl)-(4-cyclopropyl-phenyl)-methanone

A solution of 2.2 g (6.85 mmol) of(2-nitro-5-propargyloxyphenyl)-(4-cyclopropyl-phenyl)-methanol (step Cabove) in 40 ml glacial acetic acid is heated to 50° C. and treated with3.06 g (8 equiv.) of iron powder. After 5 h stirring at that temperaturethe reaction is complete. The green-grey suspension is cooled to rt,diluted by the addition of 500 ml water and 200 ml ethyl acetate andfiltered through a pad of Celite. The layers are separated and theorganic phase washed with water and sat. bicarbonate solution. Theyellow and sticky crude product is purified by chromatography(dichloromethane/MeOH) to yield a viscous yellow oil.

¹H-NMR (300 MHz, CDCl₃): 8.60 (d, 2H), 7.07-7.14 (m, 3H), 7.04 (dd, 1H),6.71 (d, 1H), 5.67 (broad, 2H), 4.53 (d, 2H), 2.48 (t, 1H), 1.91-1-2.01(m, 1H), 1.02-1.11 (m, 2H), 0.76-0.83 (m, 2H).

MS: 292 (M+1)⁺

E. Synthesis of(2-benzylamino-5-propargyloxyphenyl)-(4-cyclopropyl-phenyl)-methanone

A mixture of 490 mg (1.68 mmol) of the aniline prepared in step D, 256μl benzaldehyde and 150 μl AcOH in 5 ml MeOH is treated with 200 mg 95%sodium cyanoborohydride. Temperature is kept around rt by a coolingbath. After 5 hours the reaction mixture is distributed between waterand ethyl acetate. The crude orange oil obtained after concentrationi.V. is purified by chromatography (hexane/ethyl acetate) to yield ayellow solid. m.p. 116-118° C.

¹H-NMR (300 MHz, CDCl₃): 8.24 (d, 1H), 7.64 (d, 2H), 7.16 (dd, 1H), 7.09(d, 2H), 6.95 (d, 1H), 4.80 (d, 1H), 2.58 (t, 1H), 1.89-1.99 (m, 1H),1.03-1.10 (m, 2H), 0.76-0.83 (m, 2H).

MS: 382 (M+1)⁺

F. Synthesis of1-Benzyl-4-(4-cyclopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

A solution of 460 mg (1.21 mmol) of(2-benzylamino-5-propargyloxyphenyl)-(4-cyclopropyl-phenyl)-methanone(step E) and 118 mg (1.81 mmol) sodium cyanate in 20 ml glacial aceticacid is stirred at rt for 8 h. Then the mixture is diluted with waterand ethyl acetate. The layers are separated and the organic phase iswashed with water and bicarbonate solution. Chromatography(dichloromethane/MeOH) of the crude product affords a yellow foam. m.p.112-113° C.

¹H-NMR (300 MHz, CDCl₃): 7.72 (d, 2H), 7.46 (d, 1H), 7.18-7.35 (m, 9H),5.56 (broad, 2H), 4.63 (d, 2H), 2.55 (t, 1H), 1.95-2.05 (m, 1H),1.05-1.12 (m, 2H), 0.79-0.86 (m, 2H).

MS: 407 (M+1)⁺

The compounds of the following examples are prepared by analogy:

Example 1234-(4-Cyclopropyl-phenyl)-1-(3,3-dimethyl-butyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 159-160° C.

¹H-NMR (300 MHz, CDCl₃): 7.65 (d, 2H), 7.41-7.47 (m, 2H), 7.31 (d, 1H),7.18 (d, 2H), 4.66 (d, 2H), 4.26-4.34 (m, 2H), 2.56 (t, 1H), 1.92-2.04(m, 1H), 1.65-1.75 (m, 2H), 1.10 (s, 9H), 1.02-1.08 (m, 2H), 0.76-0.83(m, 2H).

MS: 401 (M+1)⁺

Example 1244-(4-Cyclopropyl-phenyl)-1-(3-ethoxy-4-methoxy-benzyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 66-68° C.

¹H-NMR (300 MHz, CDCl₃): 7.70 (d, 2H), 7.42-7.46 (m, 1H), 7.27-7.36 (m,2H), 7.19 (d, 2H), 6.94 (d, 1H), 6.85 (dd, 1H), 6.78 (d, 1H), 5.45(broad, 2H), 4.62 (d, 2H), 4.04 (q, 2H), 3.82 (s, 3H), 2.54 (t, 1H),1.93-2.04 (m, 1H), 1.41 (t, 3H), 1.03-1.11 (m, 2H), 0.77-0.84 (m, 2H).

MS: 481 (M+1)⁺

Example 1254-(4-Cyclopropyl-phenyl)-1-isopropyl-6-propargyloxy-1H-quinazolin-2-one

m.p. 124-125° C.

¹H-NMR (300 MHz, CDCl₃): 7.68 (d, 2H), 7.54 (d, 1H), 7.36-7.44 (m, 2H),7.18 (d, 2H), 5.20 (broad hept, 1H), 4.66 (d, 2H), 2.56 (t, 1H),1.93-2.04 (m, 1H), 1.69 (d, 6H), 1.03-1.11 (m, 2H), 0.77-0.83 (m, 2H).

MS: 359 (M+1)⁺

Example 1261-Benzyl-4-(4-cyclopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-thione

m.p. 104-106° C.

¹H-NMR (300 MHz, CDCl₃): 7.77 (d, 2H), 7.49 (t, 1H), 7.23-7.37 (m, 7H),7.20 (d, 2H), 6.22 (broad, 2H), 4.66 (d, 2H), 2.57 (t, 1H), 1.94-2.05(m, 1H), 1.05-1.13 (m, 2H), 0.78-0.85 (m, 2H).

MS: 423 (M+1)⁺

Example 1272-{3-[4-(4-Isopropyl-phenyl)-2-oxo-6-propargyloxy-2H-quinazolin-1-ylmethyl]-peony}-butyricacid

A. Synthesis of[2-(3-hydroxy-benzylamino)-5-propargyloxy-phenyl]-(4-isopropyl-phenyl)-methanone

To a solution of 267 mg (0.91 mmol)[2-(3-hydroxy-benzylamino)-5-propargyloxy-phenyl]-(4-isopropyl-phenyl)-methanonein 5 ml CH₂Cl₂ are added 122 mg (1.00 mmol) 3-hydroxy-benzaldehyd and404 μl (1.37 mmol) tetra-isopropoxy-titanium. The deep red solution isstirred for 6 h at rt. Then 289 mg (1.37 mmol) sodiumtriacetoxyborohydride and 200 μl EtOH are added and stirring iscontinued overnight. The resulting yellow-orange suspension isdistributed between water and CH₂Cl₂. Filtration of the organic layerthrough Hiflo is followed by washing with bicarbonate solution andconcentrated i.V. The crude product is purified by chromatography(hexane/ethyl acetate) to yield a red oil.

¹H-NMR (300 MHz, CDCl₃): 8.57 (broad t, NH), 7.61 (d, 2H), 7.30 (d, 2H),7.17-7.24 (m, 2H), 7.07 (dd, 1H), 6.94 (d, 1H), 6.84 (broad s, 1H), 6.72(d, 1H), 6.65 (d, 1H), 4.78 (broad s, OH), 4.51-4.53 (m, 2H), 4.43 (d,2H), 2.99 (hept, 1H), 2.47 (t, 1H), 1.39 (d, 6H).

MS: (M+1)⁺

B. Synthesis of1-(3-hydroxy-benzyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

A solution of 3.0 g (7.51 mmol) of the product prepared in step A in 45ml AcOH is treated with 732 mg (11.3 mmol) sodium cyanate. The dark redsolution is stirred for 2 h at rt. The resulting yellow-orangesuspension is diluted with water and filtered. The orange product iswashed well with water and diethyl ether to yield an orange solid. m.p.230° C.

¹H-NMR (300 MHz, DMSO-d₆): 9.36 (broad, OH), 7.68 (d, 2H), 7.36-7.49 (m,4H), 7.31-7.34 (m, 1H), 7.04-7.12 (m, 1H), 6.64 (dd, 2H), 6.58 (s, 1H),5.39 (broad s, 2H), 4.76 (d, 2H), 3.65 (t, 1H), 2.99 (hept, 1H), 2.47(t, 1H), 1.26 (d, 6H).

MS: 539 (M+1)⁺

C. Synthesis of2-{3-[4-(4-isopropyl-phenyl)-2-oxo-6-propargyloxy-2H-quinazolin-1-ylmethyl]-peony}-butyricacid ethyl ester

A suspension of 200 mg (0.47 mmol) of the phenol prepared in step B in 3ml DMF is cooled with an ice/water bath and treated with 27 mg (0.61mmol) sodium hydride. A yellow solution formed to which 83 μl (0.56mmol) 2-bromo-butyric acid ethyl ester is added after 15 minutes. Rapidreaction sets in and after another 15 minutes the reaction mixture ishydrolyzed by the addition of 2 ml water and 5 ml ethyl acetate.Extractive work-up affords a yellow resin, which is chromatographed(hexane/ethyl acetate).

¹H-NMR (300 MHz, CDCl₃): 7.75 (d, 2H), 7.48 (d, 1H), 7.38 (d, 2H), 7.30(dd, 1H), 7.22 (d, 1H), 7.19 (d, 1H), 6.91 (d, 1H), 6.85 (broad s, 1H),6.72 (dd, 1H), 5.50 (broad, 2H), 4.63 (d, 2H), 4.51 (t, 1H), 4.14 (q,2H), 3.02 (hept, 1H), 2.54 (t, 1H), 1.94 (quint, 2H), 1.32 (d, 6H), 1.20(t, 3H), 1.05 (t, 3H).

MS: 539 (M+1)⁺

D. Synthesis of2-{3-[4-(4-Isopropyl-phenyl)-2-oxo-6-propargyloxy-2H-quinazolin-1-ylmethyl]-phenoxy}-butyricacid

A solution of 140 mg (0.26 mmol) of the ester prepared in step D in 3 mlMeOH is treated with 2 ml 2N NaOH. After heating to 70° C. for 2 h, thereaction mixture is distributed between ethyl acetate and water. Theaqueous phase is adjusted to pH 1 by the addition of 1 N HCl. The crudeproduct is chromatographed (MeOH/CH₂Cl₂) to give the corresponding acid.m.p. 189° C. (dec.).

¹H-NMR (300 MHz, DMSO): 7.70 (d, 2H), 7.40-7.50 (m, 4H), 7.34 (d, 1H),7.11 (t, 1H), 6.77 (broad s, 1H), 6.69 (t, 2H), 5.40 (broad, 2H), 4.76(d, 2H), 4.29 (broad t, 1H), 3.65 (t, 2H), 3.01 (hept, 1H), 1.67-1.86(m, 1H), 1.27 (d, 6H), 0.92 (t, 3H).

MS: 511 (M+1)⁺

The compound of the following example is prepared by analogy:

Example 1282-{3-[4-(4-Isopropyl-phenyl)-2-oxo-6-propargyloxy-2H-quinazolin-1-ylmethyl]-phenoxy}-2-methyl-propionicacid

¹H-NMR (300 MHz, CDCl₃): 7.73 (d, 2H), 7.47 (d, 1H), 7.37 (d, 2H), 7.30(dd, 1H), 7.22 (dd, 1H), 7.16 (d, 1H), 6.98 (d, 1H), 6.85 (broad s, 1H),6.79 (d, 1H), 5.47 (broad, 2H), 4.63 (d, 2H), 3.00 (hept, 1H), 2.53(broad t, 1H), 1.50 (s, 6H), 1.31 (d, 6H).

MS: 511 (M+1)⁺

Example 1294-(4-Isopropyl-phenyl)-1-[2-(2-methoxy-ethoxy)-pyridin-3-ylmethyl]-6-prop-2-ynyloxy-1H-quinazolin-2-one

A. Synthesis of (2-chloro-pyridin-3-yl)-methanol

To a solution of ethyl 2-chloronicotinate (1 g, 5.39 mmol) in 10 ml EtOHat room temperature is added 2.04 g (53.9 mmol) NaBH₄ over 30 minutes inseveral portions. The solution is stirred for. The excess borohydride isquenched by the addition of methanol. The solvents are evaporated andthe residue partitioned between dichloromethane and water. The aqueousPhase is extracted 3× with 10 ml of dichloromethane. The combinedorganic layers are washed with brine, dried with MgSO₄, filtered andevaporated in vacuo to yield a light yellow oil.

¹H-NMR (300 MHz, CDCl₃): 8.42 (d, 1H), 8.04 (d, 1H), 7.40 (m, 1H), 5.41(s, 3H) 4.82 (s, 2H).

MS: 144 (M+1)⁺

B. Synthesis of [2-(2-methoxy-ethoxy)-pyridin-3-yl]-methanol

153 mg (19.2 mmol) LiH is added to 10 ml methoxyethanol and the mixtureis stirred for 5 min until evolution of gas ceases. 690 mg (4.81 mmol)(2-Chloro-pyridin-3-yl)-methanol is added followed by 110 mg (1.73 mmol)Cu and 115 mg (0.721 mmol) CuSO₄ and the mixture is stirred at 100° C.After 2 days the reaction is cooled to r.t. and filtered with help ofmethanol. After evaporation ether is added to the residue and extractedtwice with brine, then dried with Na₂SO₄, filtered and evaporated untilconstant weight is reached.

¹H-NMR (300 MHz, CDCl₃): 8.22 (m, 1H), 7.74 (d, 1H), 7.04 (m, 1H), 5.44(s, 3H) 4.82 (d, 2H), 4.68 (m, 2H), 3.92 (m, 2H), 3.58 (s, 3H).

MS: 184 (M+1)⁺

C. Synthesis of(4-isopropyl-phenyl)-(2-{[2-(2-methoxy-ethoxy)-pyridin-3-ylmethyl]-amino}-5-prop-2-ynyloxy-phenyl)-methanone

To a solution of 400 mg (2.18 mmol)[2-(2-methoxy-ethoxy)-pyridin-3-yl]-methanol in 4 ml dioxane at r.t. isadded 1.12 ml (6.55 mmol) Hünig's base followed by 170 μl (2.18 mmol)mesyl chloride and the mixture is stirred for 5 min. 641 mg (2.18 mmol)(2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone is addedto this mixture with the addition of 1 ml of dioxane. The reactionmixture is then heated to 100° C. and stirred overnight. The mixture ispartitioned between ether/water and the organic layer is washed withbrine, dried with Na₂SO₄, filtered and evaporated. Flash-chromatography(ethyl acetate/ether 1:1) yields a yellow oil

¹H NMR (300 MHz, CDCl₃): 8.04 (m, 1H), 7.56-7.64 (m, 3H), 7.30 (d, 2H),7.20 (d, 1H), 7.08 (dd, 1H), 6.84 (dd, 1H), 6.70 (d, 1H), 4.58 (m, 2H),4.46 (s, 2H), 3.80 (m, 2H), 3.44 (s, 3H), 2.98 (hept, 1H), 1.32 (d, 6H).

MS: 459 (M+1)⁺

D. Synthesis of4-(4-isopropyl-phenyl)-1-[2-(2-methoxy-ethoxy)-pyridin-3-ylmethyl]-6-prop-2-ynyloxy-1H-quinazolin-2-one

To a solution of 200 mg (0.436 mmol)(4-Isopropyl-phenyl)-(2-{[2-(2-methoxy-ethoxy)-pyridin-3-ylmethyl]-amino}-5-prop-2-ynyloxy-phenyl)-methanonein 1.5 ml acetic acid is added 28 mg (0.436 mmol) sodium cyanate. Afterstirring for 2 h the solvent is removed in vacuo and the residue ispartitioned between CH₂Cl₂ and water. The organic layer is dried andevaporated. Purification of the crude product by flash-chromatography(CH₂Cl₂/ether 3:7) affords a yellow oil.

¹H NMR (300 MHz, CDCl₃): 8.06 (d, 1H), 7.74 (d, 2H), 7.30-7.52 (m, 6H),6.78 (dd, 1H), 5.64 (s, 2H), 4.62-4.66 (m, 4H), 3.84n(dd, 2H), 3.50 (s,3H), 3.02 (hept, 1H), 2.56 (t, 1H), 1.32 (d, 6H).

MS: 484 (M+1)⁺

Example 130 Synthesis of1-[6-(2-hydroxy-ethoxy)-pyridin-2-ylmethyl]-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

A. Synthesis of 6-chloro-pyridine-2-carboxylid acid

A suspension of 4.0 g (28.8 mmol) of 6-hydroxypicolinic acid, 6.0 mlphosphorus oxychloride and 20 g phosphorus pentachloride is slowlyheated to 90° C. within 1.5 hours. Stirring is continued for another 12h. After cooling to r.t. the mixture is quenched by careful addition of1.4 ml formic acid. Concentration under HV affords 5.36 g of a darksolid which is subjected to hydrolysis in water (50 ml) in the presenceof 5.56 g (40 mmol) potassium carbonate. Extractive work-up withpetroleum ether/water and conc. i.v. results in a slightly yellow solid.m.p. 188-190° C.

¹H-NMR (300 MHz, CDCl₃): 8.17 (dd, 1H), 7.93 (t, 1H), 7.62 (dd, 1H).

MS: 158 (M+1)⁺

B. Synthesis of 6-tert-butoxy-pyridine-2-carboxylic acid

A solution of 2.70 g (17.1 mmol) of 6-chloro-pyridine-2-carboxylic acidin 200 ml THF is heated for 19 h to reflux. Then the mixture is pouredinto water and adjusted to neutral pH by the addition of citric acid.Extractive workup with ethyl acetate yields a slightly yellow solid.

¹H-NMR (300 MHz, CDCl₃): 7.72 (m, 2H), 6.94 (dd, 1H), 1.64 (s, 9H).

MS: 140 [(M+1)⁺-butene]

C. Synthesis of 6-tert-butoxy-pyridine-2-carboxylic acid methyl ester

A yellow suspension of 2.60 g (13.3 mmol) of2-tert-butoxy-pyridine-2-carboxylic acid and 2.8 g (20 mmol) potassiumcarbonate in 40 ml acetone is treated at r.t. with 2.64 g (18.6 mmol) ofiodomethane. After stirring for 4 h at 40° C. the mixture is distributedbetween water and ethyl acetate. Concentration of the organic layeraffords a yellow oil.

¹H-NMR (300 MHz, CDCl₃): 7.58-7.64 (m, 2H), 6.81 (dd, 1H), 3.94 (s, 3H),1.64 (s, 9H).

MS: 154 [(M+1)⁺-butene]

D. Synthesis of (6-tert-butoxy-pyridin-2-yl)-methanol

A solution of 2.32 g (11.1 mmol) of the ester from step C in 25 ml ofethanol is reduced by portion wise addition of 2.09 g (55.4 mmol) ofsodium borohydride. HPLC analysis after stirring at r.t. for 12 hoursshows complete reaction. The mixture is diluted with methanol andextracted with ethyl acetate/water to yield a yellow oil.

¹H-NMR (300 MHz, CDCl₃): 7.61 (dd, 1H), 6.74 (dd, 1H), 6.56 (dd, 1H),4.65 (d, 2H), 3.42 (t, 1H), 1.60 (s, 9H).

E. Synthesis of 6-tert-butoxy-pyridin-2-carbaldehyd

1.65 g (9.10 mmol) of the alcohol obtained in step D in 50 mldichloromethane is oxidised with 3.86 g (9.10 mmol) of Dess-Martinperiodinane. The reaction is complete after 12 h. The reaction mixtureis extracted with ethyl acetate/aqueous sodium thiosulphate solution andthe organic layer concentrated i.V. Flash-chromatography of the crudeproduct petroleum ether/ethyl acetate) affords a yellow oil.

¹H-NMR (300 MHz, CDCl₃): 9.91 (s, 1H), 7.67 (t, 1H), 7.50 (dd, 1H), 6.86(dd, 1H), 1.66 (s, 9H).

MS: 124 [(M+)⁺-butene]

F. Synthesis of{2-[(6-tert-butoxy-pyridin-2-ylmethyl)-amino]-5-propargyloxy-phenyl}-(4-isopropyl-phenyl)-methanone

A solution of 600 mg (2.05 mmol) of(2-amino-5-propargyloxy-phenyl)-4-isopropyl-phenyl)-methanone and 403 mg(2.25 mmol) of the aldehyde obtained in the step above in 18 mldichloromethane is treated with 872 mg (3.07 mmol) oftitanium(IV)isopropoxyde. The imine obtained after stirring overnight isreduced with 650 mg (3.07 mmol) of sodium triacetoxyborohydride in thepresence of 2.4 ml of EtOH. The crude product after extractive workupwith ethyl acetate/petroleum ether is purified by flash chromatography(ethyl acetate/petroleum ether) to yield a yellow oil.

¹H-NMR (300 MHz, CDCl₃): 7.61 (d, 2H), 7.46 (dd, 1H), 7.30 (d, 2H), 7.21(d, 1H), 7.04-7.11 (m, 1H), 6.86 (d, 1H), 6.72 (d, 1H), 6.63 (d, 1H),4.53 (d, 2H), 4.48 (d, 2H), 2.99 (hept, 1H), 2.48 (t, 1H), 1.60 (s, 9H),1.34 (d, 6H).

MS: 457 (M+1)⁺

G. Synthesis of1-[(6-tert-butoxy-pyridin-2-ylmethyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

A solution of 120 mg (0.26 mmol) of the starting material (step F) in 3ml acetic acid is cyclised with 21 mg (0.315 mmol) sodium cyanateovernight to afford the quinazolinone after flash-chromatography(hexane/ethyl acetate). m.p. 62-65° C.

¹H-NMR (300 MHz, CDCl₃): 7.72 (d, 2H), 7.46-7.50 (m, 2H), 7.43 (d, 1H),7.39 (d, 2H), 7.31 (dd, 1H), 6.90 (d, 1H), 6.52 (d, 1H), 5.56 (broad s,2H), 3.03 (hept, 1H), 2.55 (t, 1H), 1.41 (s, 9H), 1.33 (d, 6H).

MS: 482 (M+1)⁺

H. Synthesis of1-[(6-tert-pyridin-2-ylmethyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

A mixture of 60 mg (0.13 mmol) of the t-butyl ether (step G) in 6 mldichloromethane is treated with 15 μl trifluoroacetic acid and stirredovernight at it. Extractive workup with aqueous sodium bicarbonatesolution/dichloromethane yields a yellow solid. m.p. 219-222° C.

¹H-NMR (300 MHz, CDCl₃): 7.76 (d, 2H), 7.55 (d, 1H), 7.32-7.48 (m, 5H),6.50 (d, 1H), 6.23 (d, 1H), 5.38 (broad s, 2H), 4.69 (d, 2H), 3.04(hept, 1H), 2.58 (t, 1H), 1.34 (d, 6H).

MS: 426 (M+1)⁺

I. Synthesis of Synthesis of1-[6-(2-hydroxy-ethoxy)-pyridin-2-ylmethyl]-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

A suspension of 40 mg (0.094 mmol) of the pyridyl-alcohol obtained instep H, 16 mg (0.132 mmol) 2-bromoethanol and 19 mg (0.141 mmol)potassium carbonate in 4 ml acetone is stirred overnight at 70° C. Thecrude product obtained after extraction with ethyl acetate/water ispurified by flash chromatography (hexane/ethyl acetate) to yield ayellow oil.

¹H-NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.32-7.56 (m, 6H), 6.92 (d, 1H),6.68 (d, 1H), 5.53 (broad s, 2H), 4.66 (d, 2H), 4.38-4.52 (m, 2H), 3.91(broad, 2H), 3.02 (help, 1H), 2.75 (broad, OH), 2.56 (t, 1H), 1.33 (d,6H).

MS: 470 (M+1)⁺

Example 1311-[6-Chloro-pyridin-3-ylmethyl]-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

A. Synthesis of 2-bromomethyl-2-chloro-pyridine

A solution of 1.28 g (10.0 mmol) 2-chloro-5-methyl-pyridine in 25 mlcarbon tetra-chloride is treated with 1.79 g (10.0 mmol) of freshlyrecrystallised N-bromo-succinimid and 30 mg benzoyl peroxide. Themixture is heated to reflux for 17 h and filtered. The filtrate iswashed with water and concentrated. Flash chromatography (hexane/ethylacetate) results in a white low melting solid. m.p. 40-43° C.

MS: 210 (2), 208 (100), 206 (75) (chloro-bromo isotope pattern) (M+1)⁺

B. Synthesis of{2-[(6-chloro-pyridin-3-ylmethyl)-amino]-5-propargyloxy-phenyl}-(4-isopropyl-phenyl)-methanone

To a solution of 323 mg (1.10 mmol) of(2-amino-5-propargyloxy-phenyl)-4-isopropyl-phenyl)-methanone and 250 mg(1.21 mmol) of 2-bromomethyl-2-chloro-pyridine (step A) in 2 ml1,3-dimethyl-2-imidazolidinone (DMEU) 213 mg (1.54 mmol) of potassiumcarbonate are added. The reaction is complete after stirring for 2 h at60° C. The cooled yellow suspension is distributed between ethyl acetateand bicarbonate solution. Flash chromatography (hexane/ethyl acetate)affords a yellow solid. m.p. 96° C.

¹H-NMR (300 MHz, CDCl₃): 8.49 (t, 1H), 8.40 (d, 1H), 7.67 (dd, 1H), 7.61(d, 2H), 7.31 (d, 2H), 7.30 (d, 1H), 7.23 (d, 1H), 7.08 (dd, 1H), 6.59(d, 1H), 4.53 (d, 2H), 4.48 (d, 2H), 2.99 (hept, 1H), 2.48 (t, 1H), 1.31(d, 6H).

MS: 419 (M+1)⁺

C. Synthesis of1-[(6-chloro-pyridin-3-ylmethyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

A solution of 320 mg (0.764 mmol) of the starting material (step B) in 4ml acetic acid is cyclised with 74 mg (1.15 mmol) sodium cyanate. Athick suspension results after 3 h. Distribution between ethyl acetateand aqueous bicarbonate solution, concentration of the organic layer andflash chromatography (hexane/ethyl acetate) of the crude product yieldsthe title quinazolinone in the form of a yellow solid. m.p. 210° C.

¹H-NMR (300 MHz, CDCl₃): 8.44 (d, 1H), 7.72 (d, 2H), 7.67 (dd, 1H), 7.61(d, 1H), 7.38 (d, 2H), 7.36 (dd, 1H), 7.27 (d, 1H), 7.21 (d, 1H), 5.51(broad, 2H), 4.65 (d, 2H), 3.01 (hept, 1H), 2.55 (t, 1H), 1.31 (d, 6H).

MS: 444 (M+1)⁺

Example 132(4-Isopropyl-phenyl)-(2-{[6-(2-methoxy-ethoxy)-pyridin-2-ylmethyl]-amino}-5-propargyloxy-phenyl)-methanone

A. Synthesis of{2-[(6-hydroxy-pyridin-3-ylmethyl)-amino]-5-propargyloxy-phenyl}-(4-isopropyl-phenyl)-methanone

A solution of 120 mg (0.263 mmol) of{2-[(6-tert-butoxy-pyridin-2-ylmethyl)-amino]-5-propargyloxy-phenyl}-(4-isopropyl-phenyl)-methanone(see above) in 3 ml dichloromethane is treated with 30 μltrifluoroacetic acid and stirred overnight.

Workup with ethyl acetate and aqueous bicarbonate solution and flashchromatography of the crude product results in a yellow solid. m.p.189-193° C.

¹H-NMR (300 MHz, CDCl₃): 7.65 (d, 2H), 7.40 (dd, 1H), 7.33 (d, 2H), 7.24(d, 1H), 7.08 (dd, 1H), 6.58 (d, 1H), 6.45 (d, 1H), 6.24 (d, 1H), 4.55(d, 2H), 4.40 (d, 2H), 3.01 (hept, 1H, 2.49 (t, 1H), 1.32 (d, 6H).

MS: 401 (M+1)⁺

B. Synthesis of Synthesis of(4-isopropyl-phenyl)-(2-{[6-(2-methoxy-ethoxy)-pyridin-2-ylmethyl]-amino}-5-propargyloxy-phenyl)-methanone

A suspension of 50 mg (0.125 mmol) of the pyridyl-alcohol obtained instep A, 13 μl (0.137 mmol) 2-bromoethyl methyl ether and 26 mg (0.187mmol) potassium carbonate in 6 ml acetone is stirred overnight at 70° C.The crude product obtained after extraction with ethyl acetate/water ispurified by flash chromatography (hexane/ethyl acetate) to yield ayellow oil.

¹H-NMR (300 MHz, CDCl₃): 8.83 (t, NH), 7.62 (d, 2H), 7.52 (dd, 1H), 7.30(d, 2H), 7.21 (d, 1H), 7.10 (dd, 1H), 6.90 (d, 1H), 6.69 (dd, 2H), 4.60(dd, 2H), 4.53 (d, 2H), 4.48 (d, 2H), 3.78 (dd, 2H), 3.44 (s, 3H), 2.99(hept, 1H), 2.48 (t, 1H), 1.31 (d, 6H).

MS: 459 (M+1)⁺

Example 1331-(2-Hydroxy-pyridin-3-ylmethyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

A solution of 290 mg (0.635 mmol) of{2-[(2-tert-butoxy-pyridin-3-ylmethyl)-amino]-5-propargyloxy-phenyl}-(4-isopropyl-phenyl)-methanoneand in 7 ml acetic acid is reacted with 50 mg (0.762 mmol) sodiumcyanate. After stirring overnight the mixture is distributed betweenethyl acetate and aqueous bicarbonate solution. The organic layer isconcentrated to yield the title compound in the form of a yellow solid.m.p. 121-123° C.

¹H-NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.48-7.55 (m, 3H), 7.32-7.43 (m,4H), 6.26 (t, 1H), 5.48 (s, 2H), 4.66 (d, 2H, 3.02 (hept, 1H), 2.66 (t,1H), 1.33 (d, 6H).

MS: 426 (M+1)⁺

The compounds of the following examples are prepared by analogy to theexample described above:

Example 1344-(4-Isopropyl-phenyl)-1-(5-methoxy-pyridin-2-ylmethyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 136-137° C.

¹H-NMR (300 MHz, CDCl₃): 8.25 (dd, 1H), 7.68-7.74 (m, 3H), 7.42-7.48 (m,2H), 7.34-7.41 (m, 3H), 7.14 (dd, 1H), 5.60 (broad, 2H), 4.65 (d, 2H),3.84 (s, 3H), 3.02 (hept, 1H), 2.65 (t, 1H), 1.33 (d, 6H).

MS: 440 (M+1)⁺

Example 1354-(4-Isopropyl-phenyl)-1-(6-methyl-pyridin-2-ylmethyl)-6-propargyloxy-1H-quinazolin-2-one

m.p. 165-166° C.

¹H-NMR (300 MHz, CDCl₃): 7.75 (d, 2H), 7.45-7.55 (m, 3H), 7.38 (d, 2H),7.34 (dd, 1H), 7.10 (d, 1H), 7.05 (d, 1H), 5.62 (broad, 2H), 4.65 (d,2H), 3.02 (hept, 1H), 2.60 (s, 3H), 2.55 (t, 1H), 1.33 (d, 6H).

MS: 424 (M+1)⁺

Example 1361-(2-Chloro-pyridin-4-ylmethyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

¹H-NMR (300 MHz, CDCl₃): 8.35 (d, 1H), 7.77 (d, 2H), 7.57 (d, 1H), 7.41(d, 2H), 7.37 (dd, 1H), 7.24 (s, 1H), 7.16 (d, 1H), 7.06 (d, 1H), 5.62(broad s, 2H), 4.67 (d, 2H), 3.04 (hept, 1H), 2.57 (t, 1H), 1.34 (d,6H).

MS: 444 (M+1)⁺

Example 1371-(2-Chloro-pyridin-3-ylmethyl)-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

¹H-NMR (300 MHz, CDCl₃): 8.84 (d, 1H), 7.77 (d, 2H), 7.65 (d, 1H), 7.41(d, 2H) 7.31-7.39 (m, 2H), 7.16 (dd, 1H), 7.07 (d, 1H), 5.61 (s, 2H),4.67 (d, 2H), 3.91 (broad, 2H), 3.04 (hept, 1H), 2.56 (t, 1H), 1.33 (d,6H).

MS: 444 (M+1)⁺

Example 1384-(4-Isopropyl-phenyl)-1-{6-[2-(2-methoxy-ethoxy)-ethoxy]-pyridin-2-ylmethyl)-6-propargyloxy-1H-quinazolin-2-one

¹H-NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.47-7.65 (m, 3H), 7.38 (d, 2H),7.35 (dd, 1H), 6.93 (d, 1H), 6.66 (d, 1H), 5.52 (broad, 2H), 4.66 (d,2H), 4.41 (dd, 2H), 3.78 (dd, 2H), 3.79 (dd, 2H), 3.65-3.71 (m, 2H),3.54-3.60 (m, 2H), 3.39 (s, 3H), 3.02 (hept, 1H), 2.57 (t, 1H), 1.33 (d,6H).

MS: 528 (M+1)⁺

Example 1394-(4-Isopropyl-phenyl)-1-[6-(2-methoxy-ethoxy)-ethoxy)-pyridin-2-ylmethyl)-6-propargyloxy-1H-quinazolin-2-one

¹H-NMR (300 MHz, CDCl₃): 7.74 (d, 2H), 7.47-7.63 (m, 3H), 7.39 (d, 2H),7.34 (dd, 1H), 6.92 (d, 1H), 6.69 (d, 1H), 5.53 (broad, 2H), 4.66 (d,2H), 4.38-4.43 (m, 2H), 3.66-3.71 (m, 2H), 3.42 (s, 3H), 3.02 (hept,1H), 2.56 (t, 1H), 1.33 (d, 6H).

MS: 484 (M+1)⁺

Example 1405-Allyl-1-benzyl-6-hydroxy-4-(4-isopropyl-phenyl)-1H-quinazolin-2-one

A. Synthesis of 5-allyloxy-2-nitro-benzaldehyde

To a solution of 25 g (150 mmol) 5-hydroxy-2-nitro-benzaldehyde and 44.8g (299 mmol) sodium iodide in 400 ml acetone are added 51.2 ml (299mmol) N-ethyldiisopropylamine and 25.3 ml (299 mmol) allyl bromide.After stirring for 18 h at r.t. the reaction mixture is filtered and thesolvent is evaporated. Extraction of the residue with 1 M aqueoushydrochloric acid/dichloromethane followed by chromatography(hexane/ethyl acetate) yields 5-allyloxy-2-nitro-benzaldehyde.

¹H NMR (300 MHz, CDCl₃): 10.45 (s, 1H), 8.15 (d, 1H), 7.32 (d, 1H), 7.16(dd, 1H), 6.03 (ddt, 1H), 5.45 (dq, 1H), 5.37 (dq, 1H), 4.69 (dt, 2H).

B. Synthesis of(5-allyloxy-2-nitro-phenyl)-(4-isopropyl-phenyl)-methanol

A solution of 4-isopropylphenylmagnesium bromide prepared from 2.35 g(96.5 mmol) magnesium and 18.15 g (96.5 mmol) 1-bromo-4-isopropylbenzenein 80 ml THF is added slowly at −78° C. to a solution of 20 g (96.5mmol) 5-allyloxy-2-nitro-benzaldehyde in 200 ml THF. After allowing thereaction mixture to warm up to r.t. saturated aqueous ammonium chloridesolution is added. Extraction with ethyl acetate followed bychromatographic purification on silica (hexane/ethyl acetate) yields(5-allyloxy-2-nitro-phenyl)-(4-isopropyl-phenyl)-methanol.

¹H NMR (300 MHz, CDCl₃): 8.05 (d, 1H), 7.34 (d, 1H), 7.25 (d, 2H), 7.16(d, 2H), 6.88 (dd, 1H), 6.50 (s, 1H), 6.01 (ddt, 1H), 5.40 (d, 1H), 5.33(d, 1H), 4.62 (d, 2H), 2.88 (hept, 1H), 1.22 (d, 6H).

MS: 310 (M-OH)⁺

C. Synthesis of(5-allyloxy-2-nitro-phenyl)-(4-isopropyl-phenyl)-methanone

A solution of 16.38 g (50 mmol)(5-allyloxy-2-nitro-phenyl)-(4-isopropyl-phenyl)-methanol in 60 mlacetone is treated at 0° C. with 20 ml (53.4 mmol) Jones reagent. Afterstirring for 2 h at r.t. isopropanol, an aqueous solution of sodiumbisulphite and saturated aqueous ammonium chloride solution are added.Extraction with dichloromethane affords(5-allyloxy-2-nitro-phenyl)-(4-isopropyl-phenyl)-methanone.

¹H NMR (300 MHz, CDCl₃): 8.24 (d, 1H), 7.69 (d, 2H), 7.30 (d, 2H), 7.09(dd, 1H), 6.89 (d, 1H), 6.03 (ddt, 1H), 5.43 (dq, 1H), 5.36 (dq, 1H),4.65 (dt, 2H), 2.97 (hept, 1H), 1.27 (d, 6H).

D. Synthesis of(5-allyloxy-2-amino-phenyl)-(4-isopropyl-phenyl)-methanone

To an ice chilled solution of 16 g(5-allyloxy-2-nitro-phenyl)-(4-isopropyl-phenyl)-methanone in 65 mlacetic acid are added 21.8 g iron powder. A precipitate that is formedis brought into solution by addition of additional acetic acid. Afterstirring for 16 h at r.t. the reaction mixture is filtered and basifiedby addition of aqueous potassium hydroxide solution. Extraction withdichloromethane yields(5-allyloxy-2-amino-phenyl)-(4-isopropyl-phenyl)-methanone.

¹H NMR (300 MHz, CDCl₃): 7.62 (d, 2H), 7.31 (d, 2H), 7.03-6.98 (m, 2H),6.71 (d, 1H), 5.98 (ddt, 1H), 5.32 (dd, 1H), 5.25 (dd, 1H), 4.39 (d,2H), 2.99 (hept, 1H), 1.31 (d, 6H).

MS: 296 (M+1)⁺

E. Synthesis of(2-allyl-6-amino-3-hydroxy-phenyl)-(4-isopropyl-phenyl)-methanone

In a sealed tube a mixture of 50 mg (0.17 mmol)(5-allyloxy-2-nitro-phenyl)-(4-isopropyl-phenyl)-methanone, 1 ml DMEUand 1 ml water is heated by microwave irradiation to 180° C. for 30 min.Water is evaporated and the resulting solution is purified by reversedphase preparative HPLC to yield the rearranged product.

¹H NMR (300 MHz, CDCl₃): 7.79 (d, 2H), 7.30 (d, 2H), 6.81 (d, 1H), 6.60(d, 1H), 5.80 (ddt, 1H), 5.03 (dq, 1H), 5.01 (dq, 1H), 3.16 (dt, 2H),2.97 (hept, 1H), 1.28 (d, 6H).

MS: 296 (M+1)⁺

F. Synthesis of(2-allyl-6-benzylamino-3-hydroxy-phenyl)-(4-isopropyl-phenyl)-methanone

To a solution of 39 mg (0.13 mmol)(2-allyl-6-amino-3-hydroxy-phenyl)-(4-isopropyl-phenyl)-methanone and13.34 μl (13 mmol) benzaldehyde in 1.3 ml 1,2-dichlorethane and 0.3 gmolecular sieves (4 Å pore size) are added after 1 h 13 mg (0.18 mmol)sodium cyanoborohydride and 7.55 μl acetic acid (0.13 mmol). Afterstirring for 16 h at r.t. 1 M hydrochloric acid is added to destroy theexcess of hydride equivalents. By adding 1 M NaOH the mixture isbasified. The crude product obtained by extraction with dichloromethaneis purified by reversed phase preparative chromatography.

¹H NMR (300 MHz, CDCl₃): 7.78 (d, 2H), 7.31 (d, 2H), 7.28-7.16 (m, 5H),6.82 (d, 1H), 6.56 (d, 1H), 5.79 (ddt, 1H), 5.02 (dd, 1H), 5.01 (dd,1H), 4.22 (s, 2H), 3.17 (d, 2H), 2.99 (hept, 1H), 1.30 (d, 6H).

MS: 386 (M+1)⁺

G. Synthesis of5-allyl-1-benzyl-6-hydroxy-4-(4-isopropyl-phenyl)-1H-quinazolin-2-one

A solution of 15 mg (39 μmol)(2-allyl-6-benzylamino-3-hydroxy-phenyl)-(4-isopropyl-phenyl)-methanoneand 2.5 mg sodium cyanate in 0.2 ml acetic acid is stirred at r.t. for16 h. Aqueous sodium hydroxide solution is added and the product isextracted with dichloromethane.

¹H NMR (300 MHz, CDCl₃): 7.48 (d, 2H), 7.33-7.24 (m, 8H), 7.14 (d, 1H),5.65 (ddt, 1H), 5.52 (s, 2H), 5.10 (dd, 1H), 4.95 (dd, 1H), 3.20 (d,2H), 2.97 (hept, 1H), 1.28 (d, 6H).

MS: 411 (M+1)⁺

The compounds of the following examples are prepared by analogy to theexample described above:

Example 1415-Allyl-1-[3-(2-chloro-ethoxy)-4-methoxy-benzyl]-6-hydroxy-4-(4-isopropyl-phenyl)-1H-quinazolin-2-one

¹H NMR (300 MHz, d₆DMSO): 9.66 (s, 1H), 7.31 (m, 4H), 7.25 (s, 2H), 6.99(s, 2H), 6.85 (d, 1H), 6.69 (d, 1H), 5.47-5.32 (m, 1H), 5.29 (s, 2H),4.64 (d, 1H), 4.30 (d, 1H), 4.14 (t, 2H), 3.86 (t, 2H), 3.67 (s, 3H),3.03 (d, 2H), 2.94 (hept, 1H), 1.21 (d, 6H).

MS: 519 (M+1)⁺ (isotop pattern for one chloro atom)

Example 1425-Allyl-6-hydroxy-4-(4-isopropyl-phenyl)-1-thiophen-2-ylmethyl-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.45 (d, 2H), 7.39 (d, 1H), 7.31-7.23 (m, 3H),7.20 (dd, 1H), 7.11 (m, 1H), 6.93 (dd, 1H), 5.69-5.60 (m, 1H), 5.61 (s,2H), 5.13 (dt, 1H), 5.00 (dt, 1H), 3.17 (d, 2H), 2.95 (hept, 1H), 1.26(d, 6H).

MS: 417 (M+1)⁺

Example 1435-Allyl-6-hydroxy-4-(4-isopropyl-phenyl)-1-(3-methylsulphanyl-butyl)-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.47 (d, 2H), 7.38 (d, 2H), 7.25-7.22 (m, 2H),6.35 (s, broad, 1H), 5.63 (ddt, 1H), 5.05 (d, 1H), 4.90 (d, 1H), 4.40(t, 2H), 3.20 (dd, 1H), 3.18 (dd, 1H), 2.94 (hept, 1H), 2.88-2.76 (m,1H), 2.13 (s, 3H), 2.11-1.87 (m, 2H), 1.88 (d, 3H), 1.25 (d, 6H).

MS: 423 (M+1)⁺

Example 1445-Allyl-6-hydroxy-4-(4-isopropyl-phenyl)-1-(1-methyl-2-phenyl-ethyl)-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.47-7.43 (m, 3H), 7.32-7.11 (m, 8H), 6.88(broad, 1H), 5.63 (ddt, 1H), 5.00 (dd, 1H), 4.88 (m, 1H), 4.83 (dd, 1H),3.52 (dd, 1H), 3.42 (dd, 1H), 3.22 (dd, 1H), 3.18 (dd, 1H), 2.94 (hept,1H), 1.71 (d, 3H), 1.26 (d, 6H).

MS: 439 (M+1)⁺

Example 1455-Allyl-6-hydroxy-4-(4-isopropyl-phenyl)-1-pyridin-3-ylmethyl-1H-quinazolin-2-one

¹H NMR (300 MHz, d₆DMSO): 9.74 (s, 1H), 8.56 (d, 1H), 8.46 (dd, 1H),7.61 (dt, 1H), 7.39-7.31 (m, 7H), 5.51-5.41 (m, 3H), 4.70 (dd, 1H), 4.35(dd, 1H), 3.08 (d, 2H), 2.98 (hept, 1H), 1.25 (d, 6H).

MS: 412 (M+1)⁺

Example 1465-Allyl-6-hydroxy-1-(4-hydroxy-3-methoxy-benzyl)-4-(4-isopropyl-phenyl)-1H-quinazolin-2-one

¹H NMR (300 MHz, d₆DMSO): 9.71 (s, 1H), 8.93 (s, 1H), 7.35-7.30 (m, 6H),6.95 (s, 1H), 6.68-6.57 (m, 2H), 5.44 (m, 1H), 5.30 (s, 2H), 4.68 (d,1H), 4.33 (d, 1H), 3.70 (s, 3H), 3.06 (m, 2H), 2.97 (m, 1H), 1.25 (d,6H).

MS: 457 (M+1)⁺

Example 1475-Allyl-6-hydroxy-1-[2-(2-hydroxy-ethoxy)-benzyl]-4-(4-isopropyl-phenyl)-1H-quinazolin-2-one

¹H NMR (300 MHz, d₆DMSO): 9.70 (s, 1H), 7.38 (d, 2H), 7.35 (d, 2H), 7.30(d, 1H), 7.22 (td, 1H), 7.17 (d, 1H), 7.05 (d, 1H), 6.80 (t, 1H), 6.74(dd, 1H), 5.47 (ddt, 1H), 5.38 (s, 2H), 4.96 (t, 1H), 4.70 (dd, 1H),4.36 (dd, 1H), 4.12 (t, 2H), 3.79 (q, 2H), 3.09 (d, 2H), 2.98 (hept,1H), 1.25 (d, 6H).

MS: 471 (M+1)⁺

Example 1485-Allyl-6-hydroxy-1-[3-(2-hydroxy-ethoxy)-benzyl]-4-(4-isopropyl-phenyl)-1H-quinazolin-2-one

¹H NMR (300 MHz, d₆DMSO): 9.71 (s, 1H), 7.38 (d, 2H), 7.35 (d, 2H), 7.30(d, 1H), 7.24-7.18 (m, 2H), 6.82-6.76 (m, 3H), 5.46 (ddt, 1H), 5.39 (s,2H), 4.83 (t, 1H), 4.70 (dd, 1H), 4.35 (dd, 1H), 3.91 (t, 2H), 3.66 (q,2H), 3.08 (d, 2H), 2.98 (hept, 1H), 1.25 (d, 6H).

MS: 471 (M+1)⁺

Example 1495-Allyl-1-(3,5-dimethoxy-benzyl)-6-hydroxy-4-(4-isopropyl-phenyl)-1H-quinazolin-2-one

¹H NMR (300 MHz, d₆DMSO): 9.72 (s, 1H), 7.37 (d, 2H), 7.35 (d, 2H), 7.31(d, 1H), 7.22 (d, 1H), 6.36 (m, 3H), 5.47 (ddt, 1H), 5.34 (s, 2H), 4.70(dd, 1H), 4.34 (dd, 1H), 3.67 (s, 6H), 3.08 (d, 2H), 2.98 (hept, 1H),1.25 (d, 6H).

MS: 471 (M+1)⁺

Example 1501-Benzyl-6-hydroxy-4-(4-isopropyl-phenyl)-5-propyl-1H-quinazolin-2-one

A solution of 200 mg (519 μmol)(2-allyl-6-benzylamino-3-hydroxy-phenyl)-(4-isopropyl-phenyl)-methanonein 6 ml methanol is hydrogenated in the presence of Raney nickelcatalyst during 2 h at normal pressure. The catalyst is filtered off andthe filtrate is evaporated. A 100 mg portion of the residue is dissolvedin 0.6 ml acetic acid and treated with 16.7 mg (258 μmol) sodiumcyanate. for 2.5 h at r.t. The crude product obtained after extractionwith dichloromethane/aqueous sodium bicarbonate is triturated with ethylether and dichloromethane containing a small amount of methanol.

¹H NMR (300 MHz, d₆DMSO): 9.58 (s, 1H), 7.41-7.16 (m, 11H), 5.43 (s,2H), 2.99 (hept, 1H), 2.19 (m, 2H), 1.25 (d, 6H), 1.18 (m, 2H), 0.36 (t,3H).

MS: 413 (M+1)⁺

The compound of the following example is prepared by analogy to theexample described above:

Example 1516-Hydroxy-1-isobutyl-4-(4-isopropyl-phenyl)-5-propyl-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.44 (d, 2H), 7.36 (d, 1H), 7.27 (d, 2H), 7.11(d, 1H), 5.7 (broad, 1H), 4.17 (d, 2H), 2.96 (hept, 1H), 2.86 (dd, 2H),2.26 (hept, 1H), 1.31-1.19 (m, 2H), 1.27 (d, 6H), 1.01 (d, 6H), 0.46 (t,3H).

MS: 379 (M+1)⁺

Example 1525-Cyclopropylmethyl-1-(3,3-dimethyl-butyl)-6-hydroxy-4-(4-isopropyl-phenyl)-1H-quinazolin-2-one

A. Synthesis of(6-amino-2-cyclopropylmethyl-3-hydroxy-phenyl)-(4-isopropyl-phenyl)methanone

A diazomethane solution is freshly prepared by adding 515 mg (5 mmol)N-nitroso-N-methylurea in small portions to a stirred mixture of 50 mldiethyl ether and 17.5 ml 40% aqueous potassium hydroxide solution at 5°C. Ten minutes after the last addition, the organic layer is separatedoff and dried over solid potassium hydroxide. This diazomethane solutionis added to a concentrated solution of 1.00 g (3.39 mmol)(2-allyl-6-amino-3-hydroxy-phenyl)-(4-isopropyl-phenyl)-methanone indiethyl ether containing 152 mg (0.68 mmol) Pd(OAc)₂. After stirring for16 h at r.t. the reaction mixture is filtered, evaporated to dryness andpurified by flash column chromatography.

¹H NMR (300 MHz, CDCl₃): 7.78 (d, 2H), 7.29 (d, 2H), 6.77 (d, 1H), 6.55(d, 1H), 4.70 (s, 1H), 3.40 (broad, 2H), 2.96 (hept, 1H), 2.35 (d, 2H),1.27 (d, 6H), 0.88 (m, 1H), 0.38 (m, 2H), 0.09 (m, 2H).

MS: 310 (M+1)⁺

B. Synthesis of5-cyclopropylmethyl-1-(3,3-dimethyl-butyl)-6-hydroxy-4-(4-isopropyl-phenyl)-1H-quinazolin-2-one

A mixture of 100 mg (0.32 mmol)(6-amino-2-cyclopropylmethyl-3-hydroxy-phenyl)-(4-isopropyl-phenyl)methanone,40.5 μl (0.32 mmol) 3,3-dimethylbutyric aldehyde and 28.5 mg (0.45 mmol)NaCNBH₃ in 0.5 ml 1,2-dichloroethane containing 18.5 μl (0.32 mmol)acetic acid is stirred for 18 h at r.t. To destroy the excess of hydride0.1 M hydrochloric acid is added first before by the addition of 0.1 Maqueous sodium hydroxide the mixture is made alkaline. The intermediateis extracted with dichloromethane and purified by preparative reversedphase HPLC.

A 50 mg (0.13 mmol) portion of this intermediate is dissolved in 0.1 mlacetic acid and treated with 8.3 mg (0.13 mmol) sodium cyanate. Afterstirring for 3 h at r.t. the reaction mixture is extracted withdichloromethane and aqueous bicarbonate solution. The residue obtainedafter evaporation of the organic phases is triturated with diethyl etherto obtain the pure title compound.

¹H NMR (300 MHz, CDCl₃): 7.44 (d, 2H), 7.42 (d, 1H), 7.26 (d, 2H), 7.17(d, 1H), 6.18 (s, 1H), 4.28 (m, 2H), 2.96 (hept, 1H), 2.34 (d, 2H), 1.72(m, 2H), 1.28 (d, 6H), 1.09 (s, 9H), 0.70 (m, 1H), 0.35 (m, 2H), −0.08(m, 2H).

MS: 419 (M+1)⁺

The compounds of the following examples are prepared by analogy to theexample described above:

Example 1531-Benzyl-5-cyclopropylmethyl-6-hydroxy-4-(4-isopropyl-phenyl)-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 8.0 (broad 1H), 7.47 (d, 2H), 7.29-7.22 (m,8H), 7.01 (d, 1H), 5.49 (s, 2H), 2.96 (hept, 1H), 2.36 (d, 2H), 1.27 (d,6H), 0.69 (m, 1H), 0.17 (m, 2H), −0.18 (m, 2H).

MS: 425 (M+1)⁺

Example 1545-Cyclopropylmethyl-1-(3,4-dimethoxy-benzyl)-6-hydroxy-4-(4-isopropyl-phenyl)-1H-quinazolin-2-one

¹H NMR (300 MHz, d₆DMSO): 9.58 (s, 1H), 7.33 (s, 4H), 7.27 (d, 1H), 7.24(d, 1H), 6.98 (d, 1H), 6.84 (d, 1H), 6.69 (dd, 1H), 5.33 (s, 2H), 3.67(s, 3H), 3.66 (s, 3H), 2.95 (hept, 1H), 2.20 (d, 2H), 1.22 (d, 6H), 0.60(m, 1H), 0.05 (m, 2H), −0.36 (m, 2H).

MS: 485 (M+1)⁺

Example 1555-Cyclopropylmethyl-6-hydroxy-4-(4-isopropyl-phenyl)-1-(3-methoxy-benzyl)-1H-quinazolin-2-one

¹H NMR (300 MHz, d₆DMSO): 9.60 (s, 1H), 7.35 (d, 2H), 7.33 (d, 2H), 7.28(d, 1H), 7.20 (t, 1H), 7.18 (d, 1H), 6.82-6.74 (m, 3H), 5.87 (s, 2H),3.67 (s, 3H), 2.96 (hept, 1H), 2.21 (d, 2H), 1.22 (d, 6H), 0.61 (m, 1H),0.05 (m, 2H), −0.35 (m, 2H).

MS: 455 (M+1)⁺

Example 1565-Cyclopropylmethyl-1-(3,5-dimethoxy-benzyl)-6-hydroxy-4-(4-isopropyl-phenyl)-1H-quinazolin-2-one

¹H NMR (300 MHz, d₆DMSO): 9.60 (s, 1H), 7.34 (s, 4H), 7.28 (d, 1H), 7.17(d, 1H), 6.35 (s, 3H), 5.32 (s, 2H), 3.65 (s, 6H), 2.95 (hept, 1H), 2.21(d, 2H), 1.22 (d, 6H), 0.61 (m, 1H), 0.05 (m, 2H), −0.36 (m, 2H).

MS: 485 (M+1)⁺

Example 1575-Cyclopropylmethyl-6-hydroxy-1-(4-hydroxy-3-methoxy-benzyl)-4-(4-isopropyl-phenyl)-1H-quinazolin-2-one

¹H NMR (300 MHz, d₆DMSO): 9.59 (s, 1H), 8.91 (s, 1H), 7.33 (s, 4H), 7.28(d, 1H), 7.27 (d, 1H), 6.94 (d, 1H), 6.65 (d, 1H), 6.60 (dd, 1H), 5.28(s, 2H), 3.68 (s, 3H), 2.95 (hept, 1H), 2.20 (d, 2H), 1.22 (d, 6H), 0.60(m, 1H), −0.04 (m, 2H), −0.36 (m, 2H).

MS: 471 (M+1)⁺

Example 1581-[(3-(3,4-Dimethoxy-phenyl)-propyl)]-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

A. Synthesis of 3-(3,4-dimethoxy-phenyl)-propan-1-ol

A solution of 6.0 g (28.5 mmol) 3-(3,4-dimethoxyphenyl)-propionic acidin 120 ml anhydrous THF is cooled to 0° C. and treated within 15 minuteswith 42.75 ml borane THF complex (1 M solution). Stirring is continuedovernight at rt. The resulting clear solution is cooled with anice/water bath and hydrolyzed by the addition of 100 ml saturatedammonium chloride solution. Extractive work-up with diethyl etherfurnishes a colourless oil, which is purified by chromatography(hexane/ethyl acetate) to yield a colourless oil.

¹H-NMR (300 MHz, CDCl₃): 6.76-6.80 (m, 1H), 6.70-6.74 (m, 2H), 3.86 (s,3H), 3.85 (s, 3H), 3.67 (t, 2H), 2.62-2.69 (m, 2H), 1.82-1.93 (m, 2H).

MS: 197 (M+1)⁺

B. Synthesis of 3-(3,4-dimethoxy-phenyl)-propionaldehyde

A solution of 2.0 g (10.2 mmol) of the aldehyde prepared in step A in 40ml CH₂Cl₂ is oxidised in the dark by the addition of 4.32 g (10.2 mmol)Dess-Marin periodinane. The reaction is complete after 30 minutes. Thesuspension formed is taken up into 50 ml CH₂Cl₂ and washed twice withsodium bicarbonate and 20% sodium thiosulphate solution. Concentrationof the organic layer affords a beige crude product which is purified bychromatography hexane/ethyl acetate) to yield a yellow oil.

¹H-NMR (300 MHz, CDCl₃): 9.80 (t, 1H), 6.70-6.81 (m, 5H), 3.86 (s, 3H),3.85 (s, 3H), 3.87-3.94 (m, 2H), 2.72-2.80 (m, 2H).

MS: 193 (M+1)⁺

C. Synthesis of{2-[3-(3,4-dimethoxy-phenyl)-propylamino]-5-propargyloxy-phenyl}-(4-isopropyl-phenyl)-methanone

To a solution of 298 mg (1.02 mmol)2-amino-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone in 6 mlCH₂Cl₂ are added 217 mg (1.12 mmol)3-(3,4-dimethoxy-phenyl)-propionaldehyde and 450 μl (1.52 mmol)tetra-isopropoxy-titanium. The deep red solution is stirred for 7 h atrt. Then 323 mg (1.52 mmol) sodium triacetoxy-borohydride and 300 μlEtOH are added and stirring is continued overnight. The reaction mixtureis extracted with water and CH₂Cl₂ and concentrated i.V. The crudeproduct is purified by chromatography (hexane/ethyl acetate) to yield ayellow oil.

¹H-NMR (300 MHz, CDCl₃): 8.24 (broad t, NH), 7.67 (d, 2H), 7.28 (d, 2H),7.17 (d, 1H), 7.11 (dd, 1H), 6.65-6.80 (m, 4H), 4.51 (d, 2H), 3.85 (s,3H), 3.84 (s, 3H), 3.22 (q, 2H), 2.97 (hept, 1H), 2.72 (t, 2H), 2.46 (t,1H), 2.00 (quint, 2H), 1.28 (d, 6H).

MS: 472 (M+1)⁺

D. Synthesis of1-[3-(3,4-dimethoxy-phenyl)-propyl]-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-one

A solution of 338 mg (0.72 mmol) of the product prepared in step C in 6ml AcOH is treated with 70 mg (1.1 mmol) sodium cyanate. The mixture isstirred for 1.5 h at rt. A yellow product results after work-up withethyl acetate/water, which is purified by chromatography (CH₂Cl₂/MeOH)to afford a yellow foam.

¹H-NMR (300 MHz, CDCl₃): 7.67 (d, 2H), 7.45 (d, 1H), 7.36 (d, 1H), 7.35(d, 2H), 7.12 (d, 1H), 6.74-6.80 (m, 3H), 4.64 (d, 2H), 4.25-4.33 (broadm, 2H), 3.86 (s, 3H), 3.85 (s, 3H), 2.99 (hept, 1H), 2.77 (t, 2H), 2.55(t, 1H), 2.14 (quint, 2H), 1.30 (d, 6H).

MS: 497 (M+1)⁺

E. Synthesis of1-[3-(3,4-dimethoxy-phenyl)-propyl]-4-(4-isopropyl-phenyl)-6-propargyloxy-1H-quinazolin-2-thione

A mixture of 130 mg (0.26 mmol) of the quinazolinone prepared in step Dand 122 mg (0.30) mmol Lawesson reagent in 5 ml benzene is stirred for 2h at 70° C. The solution turns slightly red. Equal amounts of Lawessonreagent are added after a total of 3 and 5 h, but the reaction remainedincomplete. After extractive work-up with ethyl acetate and water,followed by chromatography of the crude material (hexane/ethyl acetate)the intermediate is obtained as a yellow oil.

¹H-NMR (300 MHz, CDCl₃): 7.71 (d, 2H), 7.47 (d, 1H), 7.30-7.40 (m, 4H),7.16 (d, 1H), 6.82 (s, 2H), 4.67 (d, 2H), 3.89 (s, 3H), 3.87 (s, 3H),2.99 (hept, 1H), 2.83 (t, 2H), 2.57 (t, 1H), 2.28 (broad, 2H), 1.29 (d,6H).

MS: 513 (M+1)⁺

The compound of the following example is prepared by analogy:

Example 1594-(4-Isopropyl-phenyl)-1-(3-phenyl-propyl)-6-propargyloxy-1H-quinazolin-2-one

¹H-NMR (300 MHz, CDCl₃): 7.69 (d, 2H), 7.46 (d, 1H), 7.28-7.38 (m, 5H),7.18-7.26 (m, 3H), 7.06 (d, 1H), 4.66 (d, 2H), 4.26-4.34 (m, 2H), 3.00(hept, 1H), 2.84 (t, 2H), 2.55 (t, 1H), 2.16 (quint, 2H), 1.31 (d, 6H).

MS: 437 (M+1)⁺

Example 160{2-[2-(3,4-dimethoxy-phenyl)-2-methyl-propylamino]-4,5-dimethoxy-phenyl}-(4-isopropyl-phenyl)-methanone

A. Synthesis of 2-3,4-dimethoxy-phenyl)-2-methyl-propionic acid ethylester

A solution of 2.00 g (8.92 mmol) ethyl-3,4-dimethoxyphenyl acetate, 2.85ml (17.84 mmol) HMPA and 3.34 ml (53.52 mmol) methyl iodide in 50 ml THFis treated at −75° C. with 51.9 ml (35.7 mmol) of a LDA solutionprepared in THF. After 18 h stirring at −75° C. the cold reactionmixture is poured into an aqueous saturated ammonium chloride solutionand extracted with ethyl acetate. After evaporation the crudedimethylated compound still containing some HMPA is obtained and isdirectly further transformed as described below.

¹H NMR (300 MHz, CDCl₃): 6.88 (dd, 1H), 6.86 (d, 1H), 6.82 (d, 1H), 4.12(q, 2H), 3.87 (s, 3H), 3.87 (s, 3H), 1.57 (s, 6H), 1.20 (t, 3H).

B. Synthesis of 2-(3,4-dimethoxy-phenyl)-2-methyl-propan-1-ol

A solution of 909 mg (ca. 2 mmol) of the crude product describeddirectly above in 5 ml toluene is treated twice with 2.69 ml (3.2 mmol)of 1.2 M DIBAH solution in toluene at 5° C. After stirring for 20 hsaturated ammonium chloride solution is added. The reaction mixture isfiltered and extracted with diethyl ether to obtain after evaporation ofthe solvent 2-(3,4-dimethoxy-phenyl)-2-methyl-propan-1-ol.

¹H NMR (300 MHz, CDCl₃): 6.94-6.91 (m, 2H), 6.85 (d, 1H), 3.90 (s, 3H),3.88 (s, 3H), 3.60 (s, 2H), 1.34 (s, 6H).

C. Synthesis of 2-(3,4-dimethoxy-phenyl)-2-methyl-propionaldehyde

A solution of 100 mg (0.476 mmol)2-(3,4-dimethoxy-phenyl)-2-methyl-propan-1-ol in 1 ml dichloromethane istreated with 202 mg (0.476 mmol) Dess-Martin reagent at rt. After 1 haqueous sodium bicarbonate and sodium thiosulphate solutions are addedand the product is extracted with dichloromethane. The organic layersare evaporated and the aldehyde is obtained in a sufficient purity to beused in reductive animations.

¹H NMR (300 MHz, CDCl₃): 9.44 (s, 1H), 6.88 (d, 1H), 6.83 (dd, 1H), 6.74(d, 1H), 3.88 (s, 6H), 1.46 (s, 6H).

D. Synthesis of{2-[2-(3,4-dimethoxy-phenyl)-2-methyl-propylamino]-4,5-dimethoxy-phenyl}-(4-isopropyl-phenyl)-methanone

After one hour stirring a mixture of 143 mg (0.476 mmol)(2-amino-4,5-dimethoxy-phenyl)-(4-isopropyl-phenyl)-methanone, 98 mg(0.476 mmol) 2-(3,4-dimethoxy-phenyl)-2-methyl-propionaldehyde, 1.1 gmolecular sieves 4 Å pore size, 5 ml 1,2-dichloroethane and 31 μl (0.476mmol) acetic acid 41 mg (0.666 mmol) NaCNBH₃ are added. Over theduration of 4 days three additional portions of 31 μl acetic (0.476mmol) and 41 mg NaCNBH₃ (0.666 mmol) are added. Excess hydride isdestroyed by addition of 1 M hydrochloric acid and the reaction mixtureis basified by means of 1 M sodium hydroxide.{2-[2-(3,4-Dimethoxy-phenyl)-2-methyl-propylamino]-4,5-dimethoxy-phenyl}-(4-isopropyl-phenyl)-methanoneis isolated by filtration followed by extraction with dichloromethaneand reversed phase preparative HPLC.

¹H NMR (300 MHz, CDCl₃): 7.50 (d, 2H), 7.28 (d, 2H), 7.13-7.00 (m, 3H),6.84 (d, 1H), 6.14 (s, 1H), 3.90 (s, 3H), 3.88 (s, 3H), 3.86 (s, 3H),3.66 (s, 3H), 3.55 (s, 2H), 2.97 (hept, 1H), 1.52 (s, 6H), 1.29 (d, 6H).

MS: 492 (M+1)⁺

The compounds of the following examples is prepared by analogy to theexample described above.

Example 161{2-[2-(3,5-Dimethoxy-phenyl)-ethylamino]-4,5-dimethoxy-phenyl}-(4-isopropyl-phenyl)-methanone

¹H NMR (300 MHz, CDCl₃): 7.53 (d, H), 7.30 (d, 2H), 7.06 (s, 1H), 6.46(d, 2H), 6.35 (t, 1H), 6.22 (s, 1H), 3.93 (s, 3H), 3.79 (s, 6H), 3.68(s, 3H), 3.50 (t, 2H), 3.03-2.94 (m, 3H), 1.31 (d, 6H).

MS: 464 (M+1)⁺

Example 162{4,5-Dimethoxy-2-[2-(3-methoxy-phenyl)-2-methyl-propylamino]-phenyl}-(4-isopropyl-phenyl)-methanone

¹H NMR (300 MHz, CDCl₃): 7.51 (d, 2H), 7.29 (d, 2H), 7.25 (t, 1H), 7.05(m, 1H), 7.02 (s, 1H), 6.99 (t, 1H), 6.75 (dd, 1H), 6.30 (s, 1H), 3.91(s, 3H), 3.78 (s, 3H), 3.67 (s, 3H), 3.40 (s, 2H), 1.53 (s, 6H), 1.30(d, 6H).

MS: 462 (M+1)⁺

Example 163{2-[2-(3,5-Dimethoxy-phenyl)-2-methyl-propylamino]-5-prop-2-ynyloxy-phenyl}-(4-isopropyl-phenyl)-methanone

¹H NMR (300 MHz, CDCl₃): 7.56 (d, 2H), 7.28 (d, 2H), 7.16 (d, 1H), 7.11(dd, 1H), 6.87 (d, 1H), 6.68 (d, 2H), 6.30 (s, 1H), 4.54 (d, 2H), 3.77(s, 6H), 3.36 (s, 2H), 2.98 (hept, 1H), 2.48 (t, 1H), 1.48 (s, 6H), 1.30(d, 6H).

MS: 486 (M+1)⁺

Example 164{2-[2-(3,5-Dimethoxy-phenyl)-ethylamino]-5-prop-2-ynyloxy-phenyl}-(4-isopropyl-phenyl)-methanone

¹H NMR (300 MHz, CDCl₃): 7.59 (d, 2H), 7.30 (d, 2H), 7.20 (d, 1H), 7.15(dd, 1H), 6.82 (d, 1H), 6.44 (d, 2H), 6.84 (t, 1H), 4.55 (d, 2H) 3.79(s, 6H), 3.48 (t, 2H). 3.03-2.93 (m, 3H), 2.49 (t, 1H), 1.31 (d, H).

MS: 458 (M+1)⁺

Example 165{2-[2-(3,4-Dimethoxy-phenyl)-ethylamino]-4,5-dimethoxy-phenyl}-(4-isopropyl-phenyl)-methanone

¹H NMR (300 MHz, CDCl₃): 7.56 (d, 2H), 7.32 (d, 2H), 7.08 (s, 1H),6.84-6.83 (m, 3H), 6.67 (broad, 1H), 3.97 (s, 3H); 3.87 (s, 3H), 3.87(s, 3H), (3.72 s, 3H), 3.49 (t, 2H), 3.08 (t, 2H), 2.99 (hept, 1H), 1.31(d, 6H).

MS: 464 (M+1)⁺

Example 1664-Ethyl-4-{[2-(4-isopropyl-benzoyl)-4,5-dimethoxy-phenylamino]-methyl}-hexanenitrile

¹H NMR (300 MHz, CDCl₃): 9.18 (m, broad, 1H), 7.55 (d, 2H), 7.30 (d,2H), 7.09 (s, 1H), 6.19 (s, 1H), 3.98 (s, 3H), 3.69 (s, 3H), 3.01 (d,2H), 2.97 (hept, 1H), 2.34-2.28 (m, 2H), 1.85-1.80 (m, 2H), 1.49 (q,4H), 1.29 (d, 6H), 0.88 (t, 6H).

Example 1671-[2-(3,5-Dimethoxy-phenyl)-ethyl]-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

A solution of 15 mg (33 μmol){2-[2-(3,5-dimethoxy-phenyl)-ethylamino]-5-prop-2-ynyloxy-phenyl}-(4-isopropyl-phenyl)-methanoneand 2.1 mg (33 μmol) NaOCN in 300 μl acetic acid is stirred for 1 h atrt. The solvent is evaporated and the product is recrystallised fromCH₂Cl₂/diethyl ether.

¹H NMR (300 MHz, CDCl₃): 7.70 (d, 2H), 7.49 (d, 1H), 7.43 (dd, 1H), 7.37(d, 2H), 7.34 (d, 1H), 6.50 (d, 2H), 6.36 (t, 1H), 4.68 (d, 2H), 4.48(dd, 2H), 3.80 (s, 6H), 3.09-2.97 (m, 3H), 2.57 (t, 1H), 1.32 (d, 6H).

MS: 483 (M+1)⁺

Example 168{2-[2-(3,5-Dimethoxy-phenyl)-2-methyl-propylamino]-4-hydroxy-5-methoxy-phenyl}-(4-isopropyl-phenyl)-methanone

A. Synthesis of(2-amino-4-hydroxy-5-methoxy-phenyl)-(4-isopropyl-phenyl)-methanone

A mixture of 1.34 g (4.48 mmol)(2-amino-4,5-dimethoxy-phenyl)-(4-isopropyl-phenyl)-methanone, 1.88 gsodium ethanethiolate and 10 ml DMF are heated for 5 h to 110° C.Saturated aqueous bicarbonate solution (10 ml) and 100 ml water areadded. The product is extracted with CH₂Cl₂ and chromatographed onsilica (hexane/ethyl acetate).

¹H NMR (300 MHz, CDCl₃): 7.56 (d, 2H), 7.30 (d, 2H), 6.96 (s, 1H), 6.31(s, 1H), 3.70 (s, 3H), 1.30 (d, 6H).

MS: 286 (M+1)⁺

B. Synthesis of{2-[2-(3,5-dimethoxy-phenyl)-2-methyl-propylamino]-4-hydroxy-5-methoxy-phenyl}-(4-isopropyl-phenyl)-methanone

A mixture of 41.1 mg (144 μmol)(2-amino-4-hydroxy-5-methoxy-phenyl)-(4-isopropyl-phenyl)-methanone, 45mg (216 μmol) 2-(3,5-dimethoxy-phenyl)-2-methyl-propionaldehyde, 180 mgmolecular sieves (pore size 4 Å) and 0.50 ml CH₂Cl₂ is stirred for 90min before 8.23 μl (144 μmol) and 22 mg NaCNBH₃ are added. After 16 hthe excess of reducing agent is destroyed by addition of 1 Mhydrochloric acid and the mixture is basified with 1 M sodium hydroxidesolution. The product is extracted with CH₂Cl₂ and purified by reversedphase preparative HPLC.

¹H NMR (300 MHz, d₆DMSO): 10.07 (s, 1H), 8.71 (t, broad, 1H), 7.40 (d,2H), 7.31 (d, 2H), 6.84 (s, 1H), 6.56 (d, 2H), 6.33 (t, 1H), 6.26 (s,1H), 3.71 (s, 6H), 3.50 (s, 3H), 3.27 (d, 2H), 2.94 (hept, 1H), 1.35 (s,6H), 1.23 (d, 6H).

MS: 478 (M+1)⁺

The compound of the following example is prepared by analogy to theexample described above:

Example 169(2-Benzo[1,3]dioxol-5-yl-ethyl)-[5-hydroxy-2-(4-isopropyl-benzoyl)-4-methoxy-phenyl]-ammonium;chloride

¹H NMR (300 MHz, CD₃OD): 7.71 (d, 2H), 7.44 (d, 2H), 7.19 (s, 1H), 6.98(m, 1H), 6.79 (s, 1H), 6.75 (s, 2H), 5.90 (s, 2H), 3.79 (s, 3H), 3.63(t, 2H), 3.08-2.99 (m, 3H), 1.32 (d, 6H).

MS: 434 (M+1)⁺

Example 170[2-(Cyclopropylmethyl-amino)-4-hydroxy-5-methoxy-phenyl]-(4-isopropyl-phenyl)-methanone

¹H NMR (300 MHz, CDCl₃): 9.17 (broad 1H), 7.55 (d, 2H), 7.29 (d, 2H),7.04 (s, 1H), 6.39 (s, 1H), 6.15 (s, 1H), 3.71 (s, 3H), 3.07 (d, 2H),2.98 (hept, 1H), 1.30 (d, 6H), 1.19 (m, 1H), 0.60 (m, 2H), 0.31 (m, 2H).

Example 1711-[2-Hydroxy-2-(2,4,6-trimethyl-phenyl)-ethyl]-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

A mixture of 0.5 g (1.57 mmol)4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one, 0.254 g(1.57 mmol) mesityl oxirane, 35.7 mg (0.157 mmol) benzyltriethylammoniumchloride and 21.7 mg (0.157 mmol) potassium carbonate is stirred in 1 mldioxane at 90° C. for 6 days. The reaction mixture is extracted withwater/dichloromethane and, after evaporation of the organic phases, theresidue is purified by preparative reversed phase HPLC.

¹H NMR (300 MHz, CDCl₃): 7.72 (d, 2H), 7.54 (d, 1H), 7.50 (d, 1H), 7.43(dd, 1H), 7.38 (d, 2H), 6.88 (s, 2H), 5.66 (dd, 1H), 4.93 (d, 1H), 4.68(d, 2H), 4.37 (dd, 1H), 3.02 (hept, 1H), 2.60 (s, 6H), 2.57 (t, 1H),2.28 (s, 3H), 1.33 (d, 6H).

MS: 481 (M+1)⁺

The compound of the following example is prepared by analogy to theexample described above:

Example 1721-[2-(3,5-Difluoro-phenyl)-2-hydroxy-ethyl]-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.67 (d, 2H), 7.49-7.43 (m, 3H), 7.37 (d, 2H),7.10 (m, 2H), 6.74 (tt, 1H), 5.81 (dd, 1H), 4.68 (d, 2H), 4.51 (dd, 2H),4.38 (dd, 2H), 3.01 (hept, 1H), 2.57 (t, 1H), 1.32 (d, 6H).

MS: 475 (M+1)⁺

Example 1734-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-1-[(E)-2-(2,4,6-trimethyl-phenyl)-vinyl]-1H-quinazolin-2-one

A solution of 50 mg (0.104 mmol)1-[2-hydroxy-2-(2,4,6-trimethyl-phenyl)-ethyl]-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-oneand 34.3 μl (0.208 mmol) trifluoromethane sulphonic anhydride in 0.5 ml1,2 dichloroethane is heated to 80° C. for 15 min. Extraction withdichloromethane/aqueous NaHCO₃ followed by preparative reversed phaseHPLC yielded the title compound.

¹H NMR (300 MHz, CDCl₃): 7.76 (d, 2H), 7.68 (d, 1H), 7.51 (d, 1H), 7.41(dd, 1H), 7.40 (d, 2H), 7.03 (d, 1H), 6.94 (s, 2H), 6.71 (d, 1H), 4.69(d, 2H), 3.03 (hept, 1H), 2.58 (t, 1H), 2.47 (s, 6H), 2.32 (s, 3H), 1.33(d, 6H).

MS: 463 (M+1)⁺

The compounds of the following examples are prepared by analogy to theexample described above:

Example 1744-(4-Isopropyl-phenyl)-6-prop-2-ynyloxy-1-((E)-styryl)-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.78 (d, 2H), 7.64 (d, 1H), 7.56-7.53 (m, 2H),7.51 (d, 1H), 7.43-7.35 (m, 6H), 7.25 (d, 1H), 7.03 (d, 1H), 4.70 (d,2H), 3.03 (hept, 1H), 2.58 (t, 1H), 1.34 (d, 6H).

MS: 421 (M+1)⁺

Example 1751-[(E)-2-(3-Chloro-4-methoxy-phenyl)-vinyl]-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H NMR (300 MHz, CDCl₃): 7.77 (d, 2H), 7.60 (d, 1H), 7.59 (s, 1H), 7.51(d, 1H), 7.41-7.37 (m, 4H), 7.13 (d, 1H), 6.96 (d, 1H), 6.92 (d, 1H),4.70 (d, 2H), 3.95 (s, 3H), 3.03 (hept, 1H), 2.58 (t, 1H), 1.33 (d, 6H).

MS: 487 (30), 485 (100) (M+1)⁺ (chlorine isotope pattern)

Example 1761-[(E)-2-(3,5-Dimethyl-phenyl)-vinyl]-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one

¹H-NMR (300 MHz, CDCl₃): 7.78 (d, 2H), 7.64 (d, 1H), 7.50 (d, 1H), 7.40(d, 2H), 7.37 (dd, 1H), 7.23 (d, 1H), 7.17 (s, 2H), 7.00 (s, 1H), 6.93(d, 1H), 4.69 (d, 2H), 3.03 (hept, 1H), 2.58 (t, 1H), 2.36 (s, 6H), 1.33(d, 6H).

MS: 449 (M+1)⁺

Example 1772-Benzylsulphanyl-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-quinazoline

A. Synthesis of4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline-2-thione

A solution of 0.5 g (1.71 mmol)(2-amino-5-prop-2-ynyloxy-phenyl)-(4-isopropyl-phenyl)-methanone and0.23 ml (1.71 mmol) benzoyl isothiocyanate in 5 ml THF is stirred for 3h at r.t. before 0.235 g potassium carbonate and 5 ml methanol areadded. After stirring for 18 h, the reaction mixture is acidified with0.1 M aqueous hydrochloric acid and extracted with dichloromethane.After evaporation of the organic phases, the residue is triturated withdiethyl ether to give the title compound.

¹H NMR (300 MHz, d₆DMSO): 13.79 (s, 1H), 7.70 (d, 2H), 7.54 (s, 2H),7.44 (d, 2H), 7.32 (s, 1H), 4.80 (s, 2H), 3.69 (s, 1H), 2.99 (hept, 1H),1.24 (d, 6H).

MS: 335 (M+1)⁺

B. Synthesis of2-benzylsulphanyl-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-quinazoline

To a solution of 100 mg (299 μmol)4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline-2-thione in 2 mlTHF are added 35.5 μl (299 μmol) benzyl bromide and 76 μl (448 μmol)DIEA. After stirring for 18 h at r.t. the reaction mixture is extractedwith dichloromethane and water. After evaporation of the organic layersthe crude product is purified by flash chromatography usinghexanes/ethyl acetate 20:1 as eluent.

¹H NMR (300 MHz, CDCl₃): 7.88 (d, 1H), 7.72 (d, 2H), 7.53-7.48 (m, 4H),7.40 (d, 2H), 7.32-7.19 (m, 3H), 4.71 (d, 2H), 4.56 (s, 2H), 3.02 (hept,1H), 2.58 (t, 1H), 1.33 (d, 6H).

The compounds of the following examples are prepared by analogy to theexample described above:

Example 1784-(4-Isopropyl-phenyl)-2-isopropylsulphanyl-6-prop-2-ynyloxy-quinazoline

¹H NMR (300 MHz, CDCl₃): 7.83 (dm, 1H), 7.73 (d, 2H), 7.57-7.51 (m, 2H),7.39 (d, 2H), 4.70 (d, 2H), 4.13 (hept, 1H), 3.01 (hept, 1H), 2.57 (t,1H), 1.50 (d, 6H), 1.32 (d, 6H).

Example 1792-Isobutylsulphanyl-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-quinazoline

¹H NMR (300 MHz, CDCl₃): 7.84 (dd, 1H), 7.75 (d, 2H), 7.51 (dd, 1H),7.49 (s, 1H), 7.40 (d, 2H), 4.72 (d, 2H), 3.22 (d, 2H), 3.03 (hept, 1H),2.58 (t, 1H), 2.08 (nonet, 1H), 1.34 (d, 6H), 1.10 (d, 6H).

The Agents of the Invention, as defined above, e.g., of formula I or II,particularly as exemplified, in free or pharmaceutically acceptable acidaddition salt form, exhibit pharmacological activity and are useful aspharmaceuticals, e.g. for therapy, in the treatment of diseases andconditions as hereinafter set forth.

Inositol Phosphate Formation Assay:

To determine antagonistic activity at the human parathyroidcalcium-sensing receptor (PcaR), compounds are tested in functionalassays measuring the inhibition of calcium-induced inositol phosphateformation in CCL39 fibroblasts stably transfected with human PcaR.

Cells are seeded into 24 well plates and grown to confluence. Culturesare then labelled with [³H]inositol (74 Mbq/ml) in serum-free medium for24 h. After labelling, cells are washed once with a modifiedHepes-buffered salt solution (mHBS: 130 mM NaCl, 5.4 mM KCl, 0.5 mMCaCl₂, 0.9 mM MgSO₄, 10 mM glucose, 20 mM HEPES, pH 7.4) and incubatedwith mHBS at 37° C. in the presence of 20 mM LiCl to block inositolmonophosphatase activity. Test compounds are added 3 minutes beforestimulating PcaR with 5.5 mM calcium and incubations continued forfurther 20 min. Thereafter, cells are extracted with 10 mM ice-coldformic acid and inositol phosphates formed are determined using anionexchange chromatography and liquid scintillation counting.

Assay for Intracellular Free Calcium:

An alternative method to determine antagonism at the PcaR consists inmeasuring the inhibition of intracellular calcium transients stimulatedby extracellular calcium. CCL39 fibroblasts stably transfected withhuman PcaR are seeded at 40,000 cells/well into 96-well Viewplates andincubated for 24 hours. Medium is then removed and replaced with freshmedium containing 2 μM Fluo-3 AM (Molecular Probes, Leiden, TheNetherlands), In routine experiments, cells are incubated at 37° C., 5%CO₂ for 1 h. Afterwards, plates are washed twice with mHBS and wells arerefilled with 100 μl mHBS containing the test compounds. Incubation iscontinued at room temperature for 15 minutes. To record changes ofintracellular free calcium, plates are transferred tofluorescence-imaging plate reader (Molecular Devices, Sunnyvale, Calif.,USA). A baseline consisting in 5 measurements of 0.4 seconds each (laserexcitation 488 nm) is recorded. Cells are then stimulated with calcium(2.5 mM final), and fluorescence changes recorded over a period of 3minutes.

When measured in the above assays, Agents of the Invention typicallyhave IC₅₀s in the range from about 50 μM down to about 10 nM or less.

It is now well established that controlled treatment of patients withparathyroid hormone (PTH) and analogues and fragments thereof can have apronounced anabolic effect on bone formation. Thus compounds whichpromote PTH release, such as the Agents of the Invention may be used forpreventing or treating conditions of bone which are associated withincreased calcium depletion or resorption or in which stimulation ofbone formation and calcium fixation in the bone is desirable.

Thus in a further aspect the invention includes a method for preventingor treating bone conditions which are associated with increased calciumdepletion or resorption or in which stimulation of bone formation andcalcium fixation in the bone is desirable in which an effective amountof an Agent of the Invention is administered to a patient in need ofsuch treatment.

In a yet further aspect the invention includes a pharmaceuticalcomposition for preventing or treating bone conditions which areassociated with increased calcium depletion or resorption or in whichstimulation of bone formation and calcium fixation in the bone isdesirable comprising an Agent of the Invention in admixture with apharmaceutically acceptable excipient, diluent or carrier.

Agents of the Invention are accordingly indicated for preventing ortreating all bone conditions which are associated with increased calciumdepletion or resorption or in which stimulation of bone formation andcalcium fixation in the bone is desirable, e.g. osteoporosis of variousgenesis (e.g. juvenile, menopausal, post-menopausal, post-traumatic,caused by old age or by corticosteroid therapy or inactivity),fractures, osteopathy, including acute and chronic states associatedwith skeletal demineralisation, osteo-malacia, periodontal bone loss orbone loss due to arthritis or osteoarthritis or for treatinghypoparathyroidism.

Further diseases and disorders which might be prevented or treatedinclude e.g. seizures, stroke, head trauma, spinal cord injury,hypoxia-induced nerve cell damage such as in cardiac arrest or neonataldistress, epilepsy, neurodegenerative diseases such as Alzheimer'sdisease, Huntington's disease and Parkinson's disease, dementia, muscletension, depression, anxiety, panic disorder, obsessive-compulsivedisorder, post-traumatic stress disorder, schizophrenia, neurolepticmalignant syndrome, congestive heart failure; hypertension; gut motilitydisorders such as diarrhoea, and spastic colon and dermatologicaldisorders, e.g. in tissue healing, for example burns, ulcerations andwounds.

The Agents of the Invention are particularly indicated for preventing ortreating osteoporosis of various genesis.

For all the above uses, an indicated daily dosage is in the range fromabout 0.03 to about 300 mg preferably 0.03 to 30, more preferably 0.1 to10 mg of a compound of the invention. Agents of the Invention may beadministered twice a day or up to twice a week.

The Agents of the Invention may be administered in free form or inpharmaceutically acceptable salt form. Such salts may be prepared inconventional manner and exhibit the same order of activity as the freecompounds. The present invention also provides a pharmaceuticalcomposition comprising an Agent of the Invention in free base form or inpharmaceutically acceptable salt form in association with apharmaceutically acceptable diluent or carrier. Such compositions may beformulated in conventional manner. The Agents of the Invention may beadministered by any conventional route, for example parenterally e.g. inform of injectable solutions or suspensions, enterally, e.g. orally, forexample in the form of tablets or capsules or in a transdermal, nasal ora suppository form.

In accordance with the foregoing the present invention further provides:

an Agent of the Invention or a pharmaceutically acceptable salt thereoffor use as a pharmaceutical;

a method for preventing or treating above mentioned disorders anddiseases in a subject in need of such treatment, which method comprisesadministering to said subject an effective amount of an Agent of theInvention or a pharmaceutically acceptable salt thereof;

c) an Agent of the Invention or a pharmaceutically acceptable saltthereof for use in the preparation of a pharmaceutical composition e.g.for use in the method as in b) above.

According to a further embodiment of the invention, the Agents of theInvention may be employed as adjunct or adjuvant to other therapy, e.g.a therapy using a bone resorption inhibitor, for example as inosteoporosis therapy, in particular a therapy employing calcium, acalcitonin or an analogue or derivative thereof, e.g. salmon, eel orhuman calcitonin, a steroid hormone, e.g. an estrogen, a partialestrogen agonist or estrogen-gestagen combination, a SERM (SelectiveEstrogen Receptor Modulator) e.g. raloxifene, lasofoxifene, TSE-424,FC1271, Tibolone (Livial®), vitamin D or an analogue thereof or PTH, aPTH fragment or a PTH derivative e.g. PTH (1-84), PTH (1-34), PTH(1-36), PTH (1-38), PTH (1-31)NH₂ or PTS 893.

When the Agents of the Invention are administered in conjunction with,e.g. as an adjuvant to bone resorption inhibition therapy, dosages forthe co-administered inhibitor will of course vary depending on the typeof inhibitor drug employed, e.g. whether it is a steroid or acalcitonin, on the condition to be treated, whether it is a curative orpreventive therapy, on the regimen and so forth.

The invention claimed is:
 1. A compound of formula I

wherein Y is O or S; R1 represents from 1 to 3 substituentsindependently selected from OH, SH, halo, NO₂, optionally substituted(lower alkyl, lower alkoxy, lower alkenyl, lower alkenyloxy, loweralkynyl, lower alkynyloxy, lower alkanoyl, cycloalkyl, loweralkylsulphone, lower alkylsulphoxide or amino); R2 represents from 1 to3 substituents selected from halo, optionally substituted (lower alkyl,lower alkenyl, cycloalkyl or lower alkoxy); R3 is a) lower alkyloptionally substituted by 1 to 3 substituents selected from cycloalkyl,lower alkylene, lower alkyl, Br, F, CF₃, CN, COOH, loweralkyl-carboxylate, OH, lower alkoxy or —O_(x)—(CH₂)_(y)—SO_(z)-loweralkyl, wherein x is 0 or 1, y is 0, 1 or 2 and z is 0, 1 or 2; or b)Benzyl which is a. mono- or di-substituted by—O_(x)—(CH₂)_(y)—SO_(z)-lower alkyl or —O_(x)—(CR, R′)_(y)—COO—R,wherein x, y and z are as defined above and R or R′ is H or lower alkyl,b. substituted by 1 or 2 substituents selected from morpholino-loweralkoxy, aryl-lower alkoxy, optionally N-lower alkyl substitutedarylamino-lower alkoxy, c. substituted at the 2-position by loweralkoxy-, hydroxy-lower alkoxy- or lower alkoxy-lower alkoxy, d.substituted on the —CH₂— group thereof; or c) optionally substituted(aryl-C₂-C₈-alkyl, aryl-C₂-C₈-alkenyl, heteroarylmethyl or4-heteroarylbenzyl); or when R1 is 2 substituents one of which is OH,and the other of which is optionally substituted (lower alkyl,cycloalkyl-lower-alkyl or lower alkenyl), R3 is H or optionallysubstituted (lower alkyl, aryl, aryl-lower alkyl, arylcycloalkyl,cycloalkyl-lower alkyl, cycloalkenyl-lower alkyl, hetereoaryl-loweralkyl, hetereoaryl, or carbonyl lower alkyl); or when R1 is2-propynyloxy and R2 is isopropyl, R3 is also benzyl which issubstituted by 1 to 3 substituents selected from lower alkyl, loweralkoxy, halo, halo-lower alkyl, e.g. CF₃; or when R1 is 2-propynyloxyand R2 is isopropyl, R3 is also benzyl which is substituted by OH and asecond and optionally third substituent selected from lower alkyl, loweralkoxy, halo, —O—CH(H or lower alkyl)-COO(H or lower alkyl); or when R1is 2-propynyloxy and R2 is cyclopropyl, R3 is also optionallysubstituted lower alkyl or benzyl; or when Y is S and R1 is as definedabove but not methoxy, R3 is also optionally substituted benzyl; or acompound selected from4-(4-isopropyl-phenyl)-1-(3,4-diamino-benzyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one,1-(2,6-dichloro-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one,1-benzyl-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline-2-thione;1-(3,5di-tert-butyl-4-hydroxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one,or1-[3-(2-hydroxy-ethoxy)-benzyl]-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline-2-thione;or a pharmaceutically-acceptable and -cleavable ester, or acid additionsalt thereof; and provided that when Y is O and R3 is lower alkyl orcycloalkyl, R3 is not isopropyl or cyclopentyl; or provided the compoundof formula I is not4-(4-isopropyl-phenyl)-6-methoxy-1-pyridin-3-ylmethyl-1.H.-quinazolin-2-one,4-(4-isopropyl-phenyl)-6-methoxy-1-pyridin-2-ylmethyl-1.H.-quinazolin-2-one,1-(6-chloro-pyridin-3-ylmethyl)-4-(4-isopropyl-phenyl)-6-methoxy-1.H.-quinazolin-2-one,4-(4-isopropyl-phenyl)-6-methoxy-1-(5-nitro-furan-2-ylmethyl)-1.H.-quinazolin-2-oneor1-[2-(1.H.-indol-2-yl)-ethyl]-4-(4-isopropyl-phenyl)-6-methoxy-1.H.-quinazolin-2-one,4-(4-isopropyl-phenyl)-6-methoxy-1-phenethyl-1H-quinazolin-2-one,1-(2-hydroxy-2-phenyl-ethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one,methanesulfonic acid2-[4-(4-isopropyl-phenyl)-2-oxo-6-prop-2-ynyloxy-2H-quinazolin-1-ylmethyl]-phenylester, or acetic acid2-[4-(4-isopropyl-phenyl)-2-oxo-6-prop-2-ynyloxy-2H-quinazolin-1-yl]-1-phenyl-ethylester, 5-allyl-6-hydroxy-1-isopropyl-4-(4-isopropyl-phenyl)-1.H.-quinazolin-2-one,1-cyclopropylmethyl-4-(o-tolyl)-6-nitro-2(1H)-quinazolinone,1-ethyl-4-(o-tolyl)-6-chloro-2(1H)-quinazolinone,1-cyclopropylmethyl-4-(o-tolyl)-6-chloro-2(1H)-quinazolinone,1-cyclopropylmethyl-4-(o-fluorophenyl)-6-chloro-2(1H)-quinazolinone,1-cyclopropylmethyl-4-(m-chlorophenyl)-6-chloro-2(1H)-quinazolinone,1-cyclopropylmethyl-4-(o-chlorophenyl)-6-nitro-2(1H)-quinazolinone.
 2. Acompound according to claim 1 of formula I′

wherein Y is O or S; R1 and R2 are as defined in claim 1; R3′ is a)lower alkyl substituted by 1 to 3 substituents independently selectedfrom —S-lower alkyl, lower alkylene, cycloalkyl, Br, F or CF₃; or b)benzyl which is a. mono- or di-substituted by—O_(x)—(CH₂)_(y)—SO_(z)-lower alkyl, wherein x is 0 or 1, y is 0, 1 or 2and z is 0, 1 or 2, b. substituted by 1 or 2 substituents selected frommorpholino-lower alkoxy, aryl-lower alkoxy, optionally N-lower alkylsubstituted arylamino-alkoxy, c. substituted at the 2-position by loweralkoxy-, hydroxy-lower alkoxy- or lower alkoxy-lower alkoxy; or c)optionally substituted (arylvinyl, arylethyl, heteroarylmethyl or4-heteroarylbenzyl); or when R1 is 2 substituents one of which is OH andthe other of which is optionally substituted (lower alkyl or loweralkenyl), R3 is H or optionally substituted (lower alkyl, aryl,aryl-lower alkyl, arylcycloalkyl, cycloalkyl-lower alkyl,cycloalkenyl-lower alkyl, hetereoaryl-lower alkyl, hetereoaryl, orcarbonyl lower alkyl); or when R1 is 2-propynyl and R2 is isopropyl, R3is also benzyl which is substituted by 1 to 3 substituents selected fromlower alkyl, lower alkoxy, halo, halo-lower alkyl, e.g. CF₃, —O—CH(H orlower alkyl)-COO(H or lower alkyl); or when R1 is 2-propynyl and R2 isisopropyl, R3 is also benzyl which is substituted by OH and a second andoptionally third subtituent selected from lower alkyl, lower alkoxy,halo, —O—CH(H or lower alkyl)-COO(H or lower alkyl); or when R1 is2-propynyl and R2 is cyclopropyl, R3 is also optionally substitutedbenzyl; or when X is S and R1 is as defined above but not methoxy, R3 isalso optionally substituted benzyl; or a compound selected from4-(4-isopropyl-phenyl)-1-(3,4-diamino-benzyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one,1-(2,6-dichloro-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one,1-benzyl-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline-2-thione;1-(3di-tert-butyl-4-hydroxy-benzyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one,or1-[3-(2-hydroxy-ethoxy)-benzyl]-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazoline-2-thione;or a pharmaceutically-acceptable and -cleavable ester, or acid additionsalt thereof; and provided that when X is O and R3 is lower alkyl orcycloalkyl, R3 is not isopropyl or cyclopentyl; or provided the compoundof formula I′ is not4-(4-isopropyl-phenyl)-6-methoxy-1-pyridin-3-ylmethyl-1.H.-quinazolin-2-one,4-(4-isopropyl-phenyl)-6-methoxy-1-pyridin-2-ylmethyl-1.H.-quinazolin-2-one,1-(6-chloro-pyridin-3-ylmethyl)-4-(4-isopropyl-phenyl)-6-methoxy-1.H.-quinazolin-2-one,4-(4-isopropyl-phenyl)-6-methoxy-1-(5-nitro-furan-2-ylmethyl)-1.H.-quinazolin-2-oneor1-[2-(1.H.-indol-2-yl)-ethyl]-4-(4-isopropyl-phenyl)-6-methoxy-1.H.-quinazolin-2-one,4-(4-isopropyl-phenyl)-6-methoxy-1-phenethyl-1H-quinazolin-2-one,1-(2hydroxy-2-phenyl-ethyl)-4-(4-isopropyl-phenyl)-6-prop-2-ynyloxy-1H-quinazolin-2-one,methanesulfonic acid2-[4-(4-isopropyl-phenyl)-2-oxo-6-prop-2-ynyloxy-2H-quinazolin-1-ylmethyl]-phenylester, or acetic acid2-[4-(4-isopropyl-phenyl)-2-oxo-6-prop-2-ynyloxy-2H-quinazolin-1-yl]-1-phenyl-ethylester, 5-allyl-6-hydroxy-1-isopropyl-4-(4-isopropyl-phenyl)-1.H.-quinazolin-2-one,1-cyclopropylmethyl-4-(o-tolyl)-6-nitro-2(1H)-quinazolinone,1-Ethyl-4-(o-tolyl)-6-chloro-2(1H)-quinazolinone,1-cyclopropylmethyl-4-(o-tolyl)-6-chloro-2(1H)-quinazolinone,1-cyclopropylmethyl-4-(o-fluorophenyl)-6-chloro-2(1H)-quinazolinone,1-cyclopropylmethyl-4-(m-chlorophenyl)-6-chloro-2(1H)-quinazolinone,1-cyclopropylmethyl-4-(o-chlorophenyl)-6-nitro-2(1H)-quinazolinone.
 3. Apharmaceutically acceptable composition comprising a compound of claim1, or a salt thereof, and a pharmaceutically acceptable excipient.